CN102724880A - Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis - Google Patents

Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis Download PDF

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CN102724880A
CN102724880A CN2010800611433A CN201080061143A CN102724880A CN 102724880 A CN102724880 A CN 102724880A CN 2010800611433 A CN2010800611433 A CN 2010800611433A CN 201080061143 A CN201080061143 A CN 201080061143A CN 102724880 A CN102724880 A CN 102724880A
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naphthane
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acid
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E·马丁伯勒
M·F·贝姆
A·R·耶格尔
田宫淳子
黄黎明
E·布拉玛查理
M·穆尔加尼
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Receptos LLC
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Abstract

Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the SlP receptor. Methods of chiral synthesis of such compounds is provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.

Description

1-phosphoric acid sphingol receptor modulators and chirality synthesis method
The cross reference of related application
The application requires to enjoy in No. the 61/261st, 282, United States serial submitting on November 13rd, 2009 and the priority of No. the 61/262nd, 474, the United States serial submitted on November 18th, 2009, and its disclosed content whole is incorporated among this paper.
Technical field
The present invention relates to the compound as the activator of 1-phosphoric acid sphingol receptor subtype 1, their synthesis method and their method that treats and/or prevents application thereof.
Background technology
S1P 1/ EDG 1Acceptor is G-G-protein linked receptor (GPCR), and is the member of endothelial cell differentiation gene (EDG) receptor family.The endogenic ligand of EDG acceptor comprises the lysophosphatide class, like 1-phosphoric acid sphingol (S1P).GPCR with all is the same, and the joint of acceptor (ligation) transmits second messenger's signal through the activation of G-albumen (α, β and γ).
Little molecule S1P 1The development of activator and antagonist provides for S1P 1The understanding of the physiological action of/S1P-receptor signal conducting system.S1P 1Lymphocyte homing (lymphocyte trafficking) is disturbed in the excitement of acceptor, and they are isolated (sequestering) in lymph node and other secondary lymphoid tissue.This causes quick and irreversible lymphocyte to reduce, and this possibly be people such as (, Immunol.Rev., 195:160-177,2003) Rosen because the acceptor joint of lymph endothelial cell and lymphocyte itself.The valuable results clinically that lymphocyte is isolated is to get rid of in their inflammation and/or autoimmune response kens from surrounding tissue.
Report S1P in addition 1Excitement promote survival people such as (, Ann.Neurol., 63:61-71,2008) Miron of oligodendrocyte progenitor cells.This activity combines with the lymphocyte isolation will be very useful at the inflammation and the autoimmune disease of treatment central nervous system.
Summary of the invention
The present invention relates to be suitable for use as S1P receptor subtype 1, S1P 1, heterocyclic compound, its preparation method and methods for using them of activator, for example in treatment by S1P 1Activating in the illness (malcondition) that mediates or go up when medical treatment need (medically indicated) S1P 1Application during activation.
Some embodiment of the present invention comprises the compound of the structure with formula I-R or I-S, or its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate:
Figure BPA00001577340400021
X can be-NR ' R " or-OR " ', and Y can for-CN ,-Cl ,-CF 3, I ,-COOH or-COOR 1
R ' can be H, C 1-4Alkyl, primary hydroxyl C 1-4Alkyl (n-hydroxy C 1-4Alkyl) ,-SO 2-R 1Or-CO-R 1R " can for H ,-SO 2-R 3, randomly by one or more R 2Substituted C 1-4Alkyl is perhaps randomly by R 4Substituted loop section, wherein this ring portion is divided into piperidyl, cyclohexyl, morpholinyl, pyrrolidinyl, imidazole radicals or phenyl.R " ' can be H, C 1-4Alkyl or-CO-R 1Perhaps; R ' and R " nitrogen-atoms that is connected with them forms and contains 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic; wherein; this extra hetero atom is O or N, and wherein this heterocycle is independently selected from randomly that following substituting group list replaces or is polysubstituted :-OH, oxo (oxo) ,-NH 2, primary hydroxyl-C 1-4Alkyl ,-COOH ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1,-N (R 1R 1) and-(CH 2) m-CO-N (R 5R 5).
Each R 1Can be C independently 1-4Alkyl or H, and each R 2Can be independently H, halogen, OH, oxo ,=NH, NH 2,-COOH, F ,-NHR 1,-N (R 5R 5) ,-SO 2-R 1,-SO 2-N (R 5R 5) ,-N (R 1)-SO 2-R 1,-COOR 1,-OCO-R 1,-CO-N (R 5R 5) ,-N (R 1)-COR 1, C 1-3Alkyl, C 1-3Alkoxyl and randomly by R 4Substituted loop section, wherein this ring portion is divided into piperazinyl, piperidyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazole radicals, benzimidazolyl, azetidinyl, cyclobutinyl or phenyl.
Each R 3Can be R independently 2, C 1-4Alkyl, C 3-6Cycloalkyl or randomly by one or more R 2Substituted C 1-4Alkyl; And each R 4Can be independently halogen, OH ,-NH 2,-NHR 1,-N (R 1R 1) ,-COOH ,-COOR 1,-NHCO-R 1Each R 5Can be C independently 1-4Alkyl or H, perhaps two R 5Can form with the nitrogen-atoms that their connect and contain 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic, wherein this extra hetero atom is O or N, wherein this heterocycle randomly by-OH ,-NH 2,-N (R 1R 1), primary hydroxyl C 1-4Alkyl ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1Replace.Each m is 0,1,2 or 3 independently.
In some embodiments, the pharmaceutical composition that comprises compound of the present invention and suitable excipient is provided.
The method for using of the pharmaceutical preparation that comprises The compounds of this invention is provided in some embodiments.
In some combination, the drug regimen that comprises the compound of the present invention and second medicine (pharmaceutical combination) is provided.In each embodiment, the medical indication of said second medicine is treatment multiple sclerosis, graft rejection, acute respiratory distress syndrome or adult respiratory distress syndrome (ARDS).
In some embodiments, provide and activated the perhaps method of exciting 1-phosphoric acid sphingol receptor subtype 1, comprised this receptor hypotype 1 is contacted with the compound of claim 1.In each embodiment, the compound of claim 1 activates or exciting 1-phosphoric acid sphingol receptor subtype 1 reaches the degree that is higher than said compound activation or exciting 1-phosphoric acid sphingol receptor subtype 3.
In some embodiments, provide in treatment patient's the medical treatment and needed S1P 1The method of the illness of the activation of acceptor or excitement.In each embodiment, selective activation or exciting S1P 1Acceptor is for example with respect to S1P 3Acceptor is that medical treatment upward needs.In each embodiment, said illness comprises multiple sclerosis, graft rejection or acute respiratory distress syndrome.
The method of the synthetic specific compound (comprising compound of the present invention) of chirality is provided in some embodiments.In other some embodiment, the invention provides some midbody compound relevant with this type chirality synthesis method.
Detailed Description Of The Invention
Some embodiment of the present invention comprises the compound of the structure with formula I-R or I-S, or its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate:
Figure BPA00001577340400041
X can be-NR ' R " or-OR " ', and Y can for-CN ,-Cl ,-CF 3, I ,-COOH or-COOR 1R ' can be H, C 1-4Alkyl, primary hydroxyl C 1-4Alkyl ,-SO 2-R 1Or-CO-R 1R " can for H ,-SO 2-R 3, randomly by one or more R 2Substituted C 1-4Alkyl is perhaps randomly by R 4Substituted loop section, wherein, this ring portion is divided into piperidyl, cyclohexyl, morpholinyl, pyrrolidinyl, imidazole radicals or phenyl.R " ' can be H, C 1-4Alkyl, or-CO-R 1Perhaps; R ' and R " nitrogen-atoms that is connected with them forms and contains 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic; wherein; so extra hetero atom is O or N; wherein, and this heterocycle is independently selected from randomly that following substituting group list replaces or is polysubstituted :-OH, oxo ,-NH 2, primary hydroxyl-C 1-4Alkyl ,-COOH ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1,-N (R 1R 1) and-(CH 2) m-CO-N (R 5R 5).
Each R 1Can be C independently 1-4Alkyl or H, and each R 2Can be independently H, halogen, OH, oxo ,=NH, NH 2,-COOH, F ,-NHR 1,-N (R 5R 5) ,-SO 2-R 1,-SO 2-N (R 5R 5) ,-N (R 1)-SO 2-R 1,-COOR 1,-OCO-R 1,-CO-N (R 5R 5) ,-N (R 1)-COR 1, C 1-3Alkyl, C 1-3Alkoxyl and randomly by R 4Substituted loop section, wherein this ring portion is divided into piperazinyl, piperidyl, morpholinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazole radicals, benzimidazolyl, azetidinyl, cyclobutinyl or phenyl.
Each R 3Can be R independently 2, C 1-4Alkyl, C 3-6Cycloalkyl or randomly by one or more R 2Substituted C 1-4Alkyl; And each R 4Can be independently halogen, OH ,-NH 2,-NHR 1,-N (R 1R 1) ,-COOH ,-COOR 1,-NHCO-R 1Each R 5Can be C independently 1-4Alkyl or H, perhaps two R 5The nitrogen-atoms that connects with their can form and contain 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic, and wherein this extra hetero atom is O or N, wherein this heterocycle randomly by-OH ,-NH 2,-N (R 1R 1), primary hydroxyl C 1-4Alkyl ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1Replace.Each m is 0,1,2 or 3 independently.
In some embodiments, compound of the present invention has the structure of formula I-R, or has the structure of its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.In other embodiments, compound of the present invention has the structure of formula I-S, or has the structure of its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
In some embodiments, the invention provides the basic optically pure compound that is.
In some embodiments; The invention provides compound, this compound has than the EC of this compound as the activator of mutant S1P receptor subtype 1 (it has single sudden change with respect to wild-type receptor S1P receptor subtype 1 so that the 101st amino acid residue becomes alanine by asparagine) as the activator of wild type S1P receptor subtype 1 50Little at least ten times EC 50
In some embodiments; The invention provides compound, this compound has than the EC of this compound as the activator of mutant S1P receptor subtype 1 (it has single sudden change with respect to wild-type receptor S1P receptor subtype 1 so that the 101st amino acid residue becomes alanine by asparagine) as the activator of wild type S1P receptor subtype 1 50Little twentyfold at least EC 50
In some embodiments; The therapeutic index that the invention provides the rat of after the administration with said compound 5 or 14 days, measuring is at least 5 compound; Wherein, said therapeutic index is calculated as the ratio of maximum dose that (i) realize that when this 5 or 14 days administration finishes lung and the increase of whole opisthosoma anharmonic ratio be less than or equal to 10% this compound and the dosage of this compound of (ii) in rat, realizing 50% lymphocyte minimizing.In some embodiments, this therapeutic index is at least 10, and in some embodiments, said therapeutic index is at least 20.In some embodiments, the therapeutic index of compound is than at least 5 times greatly of the therapeutic indexs of the enantiomer of this compound.
In some embodiments; The invention provides therapeutic index the rat of after the administration of rat with said compound 5 or 14 days, measuring and be at least 5 compound, wherein said therapeutic index is calculated the ratio of maximum dose that (i) realize that when this 5 or 14 days administration finishes lung and the increase of whole opisthosoma anharmonic ratio be less than or equal to 10% this compound and the dosage of this compound of (ii) in rat, realizing 50% lymphocyte minimizing.In some embodiments, this therapeutic index is at least 10, and in some embodiments, said therapeutic index is at least 20.In some embodiments, the therapeutic index of compound is greater than the therapeutic index of the enantiomer of this compound.In some embodiments, the therapeutic index of compound be this compound enantiomer therapeutic index at least 150%.
In some embodiments, the invention provides wherein that Y is the compound of Cl, in other embodiments, the invention provides wherein, Y is CF 3Compound, and in other embodiments, the invention provides wherein, Y is the compound of CN.In some embodiments, the invention provides wherein, Y is the compound of I.In some embodiments, the invention provides the compound of Y wherein for-COOH.In some embodiments, the invention provides wherein, Y is-COOR 1Compound.
In some embodiments, the invention provides X wherein and be-NR ' R " compound, in other embodiments, the invention provides X wherein and be-OR " ' compound.In some embodiments, the invention provides X and be-OR " ' compound.In some embodiments, the invention provides the compound of X wherein, and in other embodiments, the invention provides wherein X and be-OCO-R for-OH 1Compound.
In some embodiments, the invention provides wherein R 1Be C 1-3The compound of alkyl; In other embodiments, the invention provides wherein, R ' is the compound of H.
In some embodiments, the invention provides wherein, R ' is-COR 1Compound; In other embodiments, the invention provides wherein, R ' is SO 2-R 1Compound.In some embodiments, the invention provides wherein R and " be the compound of H.
In some embodiments, the invention provides wherein R " for-SO 2-R 3Compound; In other embodiments, the invention provides wherein R and " be C 1-4The compound of alkyl, wherein said C 1-4Alkyl randomly by one or more by R 2The substituting group of definition replaces.In some embodiments, the invention provides wherein R " for-(CR aR b) n-R 2Compound, and each R aWith each R bCan be any one in H, hydroxyl and the methyl independently, perhaps at R aAnd R bBe connected under the situation on the identical carbon, they can form oxo (that is the carbon that, is connected with them forms carbonyl moiety) together.In some such embodiment, n can be 0,1,2 or 3, and in some embodiments, n is 2.In some such embodiment, R 2Can for-OH ,-NH 2,-NHR 1,-N (R 5R 5) or-COOH.
In some embodiments, the invention provides wherein R 3For randomly by one or more R 2Substituted C 1-4The compound of alkyl.In some embodiments, the invention provides wherein R 2Compound for OH; In other embodiments, the invention provides wherein R 2Be C 1-3The compound of alkoxyl.In some embodiments, the invention provides wherein R 3Be (CH 2) 2-OR 1Compound.
In some embodiments, the invention provides wherein, Y is that CN and X are-NH-SO 2-R 3Compound.In some embodiments, the invention provides wherein R 3For-C 2H 5-N (R 5R 5) or-CH 2-CO-N (R 5R 5) compound.In some embodiments, the invention provides wherein, Y is that CN and X are-NH-CO-N (R 5R 5) compound.
In some embodiments, X is-NH 2, and in some such embodiment, Y is CN.
In some embodiments, the invention provides one or more compounds among the compound 1-55:
Figure BPA00001577340400071
Figure BPA00001577340400081
Figure BPA00001577340400091
Figure BPA00001577340400101
Figure BPA00001577340400111
Figure BPA00001577340400121
Perhaps its any pharmaceutically acceptable salt, dynamic isomer, stereoisomer, solvate, hydrate or prodrug.In some such embodiment, the invention provides be selected from compound 8,13,29,33,37 and 49 or its any pharmaceutically acceptable salt, ester, dynamic isomer, stereoisomer, solvate, hydrate, homologue or prodrug in compound.
In some embodiments, the compound of formula I of the present invention is provided, wherein said compound has at least one chiral centre and is optically pure basically.
The pharmaceutical composition of the compound that comprises formula I of the present invention and suitable excipient is provided in other embodiments.
In other embodiments, the drug regimen that comprises the compound of the present invention and second medicine is provided.In other embodiment again, the drug regimen that comprises the compound of the present invention and second medicine is provided, wherein, the medical indication of said second medicine is treatment multiple sclerosis, graft rejection or an adult respiratory distress syndrome (ARDS).
In some embodiments, provide compound of the present invention to be used to prepare the application method of medicine.
In some embodiments, provide through 1-phosphoric acid sphingol receptor subtype 1 being contacted with the compound of the present invention of effective dose activate or the method for exciting 1-phosphoric acid sphingol receptor subtype 1.In further embodiment; Provide through 1-phosphoric acid sphingol receptor subtype 1 is contacted with the compound of the present invention of effective dose and activated the perhaps method of exciting 1-phosphoric acid sphingol receptor subtype 1; Wherein, said compound activation or exciting 1-phosphoric acid sphingol receptor subtype 1 reach the degree that is higher than said compound activation or exciting 1-phosphoric acid sphingol receptor subtype 3.In further embodiment; Provide through 1-phosphoric acid sphingol receptor subtype 1 is contacted with the The compounds of this invention of effective dose and activated the perhaps method of exciting 1-phosphoric acid sphingol receptor subtype 1, wherein said 1-phosphoric acid sphingol receptor subtype 1 is in the mammalian body of living, to handle (dispose).
In some embodiments; The method of the activation that needs 1-phosphoric acid sphingol receptor subtype 1 in treatment patient's the medical treatment or exciting illness is provided, and it is through being that the patient provides the frequency of beneficial effect and duration to carry out to the compound of the present invention that the patient uses effective dose to be enough to.In further embodiment; The method of the activation that needs 1-phosphoric acid sphingol receptor subtype 1 in treatment patient's the medical treatment or exciting illness is provided; It is through being that the patient provides the frequency of beneficial effect and duration to carry out to the compound of the present invention that the patient uses effective dose to be enough to, and is that medical treatment is gone up and needed with respect to the selective activation of the S1P hypotype 1 of other hypotype of S1P acceptor or excitement wherein.more further in the embodiment; The method of the activation that needs 1-phosphoric acid sphingol receptor subtype 1 in treatment patient's the medical treatment or exciting illness is provided; It is through to be patient's frequency and duration that beneficial effect is provided use the compound of the present invention of effective dose to the patient to be enough to, and wherein said illness comprises the repulsion of transplant organ or tissue; The graft versus host disease(GVH disease) that causes by transplanting; Autoimmunity syndrome comprises rheumatoid arthritis; Acute respiratory distress syndrome; Adult respiratory distress syndrome (ARDS); Influenza; Cancer; Systemic loupus erythematosus; Hashimoto thyroiditis; Lymphocytic thyroiditis; Multiple sclerosis; Myasthenia gravis; I type and type ii diabetes; Uveitis; Posterior uveitis; The uveitis relevant with Behcet's disease; Uveomeningitis; Allergic encephalomyelitis; Chronic graft angiosis (chronic allograft vasculopathy); Infect back autoimmunity disease (post-infectious autoimmune disease), comprise rheumatic fever and infect the back glomerulonephritis; Struvite proliferative skin disorders; The epidermis performance (cutaneous manifestations of immunologically-mediated disorders) of immunologically mediated disease; Trichophytosis; Atopic dermatitis; Osteomyelitis; Contact dermatitis; Eczematous dermatitis; Seborrhea; Lichen planus; Pemphigus; Bullous pemphigoid; Epidermolysis bollosa; Nettle rash; Angioedema; Vasculitis; Erythema; Epidermis eosinophilia (cutaneous eosinophilia); Acne; Alopecia areata; Keratoconjunctivitis; Spring conjunctivitis; Keratitis; Herpetic keratitis; Dystrophia epithelialis corneae; Albugo; Ocular pemphigus; Mooren's ulcer; Ulcerative keratitis; Sclerotitis; Ge Leifusishi illness in eye; Vogt-Koyanagi-Harada syndrome; Sarcoidosis; Pollen hypersensitivity symptom; Reversible obstructive airway disease; Bronchial astehma; Allergic asthma; Intrinsic asthma; Extrinsic asthma; Dust asthma; Chronic or long-term asthma (inveterate asthma); Late-onset asthma and air flue reaction under high pressure; Bronchitis; Stomach ulcer; Ischemic enteropathy; The property intestinal disease; NEC; The intestinal tract injury that thermal burn is relevant; Celiac disease; Rectitis; The eosinophilic gastroenteritis; Mastocytosis; Crohn's disease; Ulcerative colitis; The injury of blood vessel that causes by ischemic disorders and thrombosis; Atherosclerotic; Fatty heart; Myocarditis; Miocardial infarction; Arteriosclerosis; Aortitis syndrome; The cachexia that causes by virus disease; Vascular thrombosis disease; Antimigraine; Rhinitis; Eczema; Interstitial nephritis; The ephrosis that IgA-induces; Goodpasture's syndrome; Hemolytic uremic syndrome; Nephrosis; Glomerulosclerosis; Glomerulonephritis; Polymyositis; Guillain-Barre syndrome; Plum Ni Ershi is sick; Polyneuritis; Multiple neuritis; Mononeuritis; Radiculopathy; Hyperthyroidism; Basedow's disease; Thyrotoxicosis; Pure red cell aplasia; Alpastic anemia; Hypoplastic anemia; ITP; Autoimmune hemolytic anemia; Agranulocytosis; Pernicious anaemia; Megaloblastic anemia; Red blood cell takes place can not; Osteoporosis; Sarcoidosis; Fibroid lung; Idiopathic interstitial pneumonia; Dermatomyositis; Vitiligo vulgaris is sick; Ichthyosis vulgaris; Photo-allergy responsive (photoallergic sensitivity); CTCL; Polyarteritis nodosa; Hungtington's chorea; Sydenham's chorea; Myocardosis; Chorionitis; Granuloma gangraenescens; House Glenn syndrome; Adiposis; Acidophic cell property fascitis; Gums, periodontium, alveolar bone, cemental damage; Male pattern alopecia or alopecia senilis; Muscular dystrophy; Pyoderma; Sai Zeli syndrome; Chronic adrenal insufficiency; Addison's disease; The organ ischemia reperfusion injury that takes place during maintenance (ischemia-reperfusion injury of organs which occurs upon preservation); Endotoxin shock; Pseudomembranous colitis; By medicine or radiation-induced colitis; Ischemic acute renal insufficiency; Chronic renal insufficiency; Lung cancer; The malignant tumour in lymph source (malignancy of lymphoid origin); Acute or chronic lymphocytic leukemia (acute or chronic lymphocytic; Leukemias); Lymphoma; Psoriasis; The inflammatory injury of lungs; Pulmonary emphysema; Cataract; Pneumoconiosis siderotica; Retinal pigment degeneration; Senile macular degeneration; Vitreum scar (vitreal scarring); Inflammatory eye disease; The corneal alkali burn; Dermatitis erythema (dermatitis erythema); Epidermolysis skin sick (ballous dermatitis); Cement dermatitis; Gingivitis; Periodontitis; Septicemia; Pancreatitis; Carninomatosis becomes; Metastasis of cancer; Hypobaropathy; Oneself immunity hepatitis; Primary biliary cirrhosis of liver; Sclerosing cholangitis; Liver divides excision; Acute hepatic necrosis; Cirrhosis; Alcoholic cirrhosis; Hepatic failure; FHF; Tardy property hepatic failure; Slow extra urgaent dispatch hepatic failure.more further in the embodiment, said illness is one or more in the following disease: the repulsion of transplant organ or tissue; The graft versus host disease(GVH disease) that causes by transplanting; Autoimmunity syndrome comprises rheumatoid arthritis, multiple sclerosis, myasthenia gravis; Pollen hypersensitivity symptom; Type i diabetes; Psoriasic prevention; Crohn's disease; Ulcerative colitis; Acute respiratory distress syndrome; Adult respiratory distress syndrome (ARDS); Influenza; Infect the back autoimmunity disease, comprise rheumatic fever and infect the back glomerulonephritis; And metastasis of cancer.more further in the embodiment, said illness is a kind of in the following disease: influenza, ulcerative colitis, multiple sclerosis, graft rejection, acute respiratory distress syndrome or adult respiratory distress syndrome (ARDS).
In some embodiments, provide compound of the present invention to be used to prepare to be suitable for treating the application method of medicine of disease or the illness of the activation that needs 1-phosphoric acid sphingol receptor subtype 1 in the wherein medical treatment or inhibition.
In some embodiments, the invention provides and be used for that chirality is synthetic to be included in the method for compound that the hexa-atomic saturated rings of naphthane part has the naphthane part of chiral carbon, wherein said compound is about the enrichment of said chiral carbon enantiomer.In such embodiment, method of the present invention provides following steps: the compound that comprises the naphthane part (i) is provided, needs the substituted ring carbon of chirality on this carbon, to be replaced by oxo in the hexa-atomic saturated rings of wherein wherein said naphthane part; (ii) make the reaction of this compound and chiral reagent with before be connected the carbon place formation chiral centre of the naphthane part of oxo group.In some such embodiment, said chiral reagent be RuCl (cymene) [(R, R)-Ts-DPEN] or RuCl (cymene) [(S, S)-Ts-DPEN].
In some such embodiment, the said compound that comprises naphthane part that in step (i), provides and chiral reagent are reacted to form the intermediate of formula VI-R or VI-S in (ii) in step:
Figure BPA00001577340400151
Wherein, Z be-CN ,-Cl or-CF 3In some such embodiment, Z is-CN.
In some embodiments, the invention provides the method for the step of the azido naphthane that comprises the chiral configuration upset formation formula VII-S or the VII-R that connect the chiral carbon that is arranged in the hexa-atomic saturated rings of naphthane part on the oxo group before making it through the intermediate of handling formula VI-R or VI-S with diphenyl phosphate azide (DPPA):
Figure BPA00001577340400152
Wherein, Azido substituting group in the hexa-atomic saturated rings of said naphthane part has replaced the hydroxyl substituent of formula VI-R or VI-S, and the substituent chiral carbon of resulting connection azido have said chiral carbon before opposite chiral configuration when being connected to hydroxyl substituent.
In some embodiments; The invention provides the method for Z wherein for-CN; And this method comprises that further extra step (a) is formed on substituted 1 on the naphthane part; 2; The 4-oxadiazole; It makes VII-R or VII-S intermediate and protectant reaction through (a), and the formula VII-R of gained protection form or the intermediate of VII-S are reacted on the phenyl carbons that is connected Z, to form hydroxyamidines with azanol or hydroxylamine hydrochloride, and the compound of this reaction gained has formula VIII-R or VIII-S:
Figure BPA00001577340400161
(b) intermediate of formula VIII-R or VIII-S is contacted to form formula IX-R or XI-S compound with coupling agent with substituted benzoic acid:
Figure BPA00001577340400162
Wherein, X as above defines, and perhaps in some embodiments, it is OH, N 3, NH-PG, NH 2Or NR ' R "; PG can be blocking group; R ' can be H, C 1-4Alkyl, primary hydroxyl C 1-4Alkyl ,-SO 2-R 1Or-CO-R 1R " can for H ,-SO 2-R 3, randomly by one or more R 2Substituted C 1-4Alkyl is perhaps randomly by R 4Replace loop section, wherein this ring portion is divided into piperidyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazole radicals or phenyl; R aBe low alkyl group, and R 1, R 2, R 3And R 4As above define, carry out.In some such embodiment, the compound of formula IX-R or IX-S has following structure:
Figure BPA00001577340400163
In some such embodiment, said coupling agent can be for comprising the mixture of hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC).
Blocking group can be so that the chemical functional group be inertia to specific reaction conditions, and can attached middle school removes in this functional group in the molecule and from this functional group of molecule and do not destroy the remainder of said molecule basically.The practitioner of this area knows sth. or sb. thoroughly to the suitable protection base that is used for synthesis method of the present invention.Referring to, for example Greene and Wuts, Protective Groups in Organic Synthesis (blocking group in the organic synthesis), 2 NdEd., John Wiley & Sons, New York, 1991.
In some embodiments, the invention provides the compound that wherein in step (i), provides does
Figure BPA00001577340400171
approach.
In some embodiments, the invention provides the wherein method of the compound enantiomer enrichment at least 90% that is included in the naphthane part that has chiral carbon in the naphthane hexa-atomic saturated rings partly of gained.In some such embodiment, described compound enantiomer enrichment at least 95%.In some such embodiment, described compound enantiomer enrichment at least 98%.In some such embodiment, described compound enantiomer enrichment at least 99%.
In some such embodiment; The invention provides be used for the synthetic hexa-atomic saturated rings that is included in the naphthane part of chirality have chiral carbon the naphthane part chipal compounds or be included in the method that has the chipal compounds of chiral carbon De oxadiazole-naphthane part in the hexa-atomic saturated rings of naphthane part, the enantiomer enrichment of wherein said chipal compounds is at least 75%, 85%, 90%, 95%, 98% or 99%.
In some such embodiment, the invention provides the method for the chipal compounds of the present invention that is used for synthetic enantiomer enrichment at least 75%, 85%, 90%, 95%, 98% or 99%.
In some embodiments, the invention provides the compound that can be used as the intermediate of describing in this article that is used for the synthetic method of chirality.In some such embodiment, the invention provides one or more following midbody compounds:
Figure BPA00001577340400181
In some such embodiment; The invention provides and be used for the method that the synthetic hexa-atomic saturated rings that is included in the naphthane part has the naphthane compound partly of chiral carbon; Wherein said compound is about the enrichment of said chiral carbon enantiomer, and this method comprises the step that a kind of such midbody compound is provided.
In some embodiments, provide to be used for the method that the synthetic hexa-atomic saturated rings that is included in the naphthane part has the naphthane compound partly of chiral carbon, wherein said compound is about the enrichment of said chiral carbon enantiomer.In some embodiments, the method that comprises the step that the compound with structure of describing in this article is provided is provided.
In some embodiments, the invention provides the method for the compound that is used for synthesis type IX-R or XI-S:
Figure BPA00001577340400191
Wherein, X such as in this article definition, this method comprises the step that a kind of aforesaid midbody compound is provided.In some such embodiment, the invention provides the method that is used for synthetic compound of the present invention.
In some embodiments, the invention provides the structure that is used for chirality synthesis type IX-R or IX-S, or the method for its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
Figure BPA00001577340400192
Wherein, X as above defines, and wherein said compound is about the enrichment of chiral carbon enantiomer.In such embodiment, method of the present invention provides following steps:
(i) compound is provided
Figure BPA00001577340400201
(ii) make this compound and chiral reagent RuCl (cymene) [(R, R)-Ts-DPEN] or RuCl (cymene) [(S, S)-Ts-DPEN] reaction; With
(iii) before connect the naphthane part of oxo group the carbon place form chiral centre.
Synthesis method disclosed herein can adopt the extra step that is used to prepare such compound, comprises other method that is recrystallized and is used for purifying.
As used in specification and appended claim, " a kind of " of singulative, " one " comprise a plurality of indicants, only if in context, clearly indicate really not so.
As used in this article, " individuality " (as employed the experimenter of treatment) represented mammal and nonmammalian simultaneously.Mammal comprises, for example, and the mankind; Inhuman primate is like anthropoid cape and monkey; Ox; Horse; Sheep and goat.Nonmammalian comprises, for example, and fish and birds.
Like employed term " S1P in this article 1" refer to 1-phosphoric acid sphingol receptor subtype 1, and other 1-phosphoric acid sphingol receptor subtypes are mentioned with corresponding form, are called " S1P like 1-phosphoric acid sphingol receptor subtype 3 3".
As known in the art; " acceptor " is a kind of biomolecule entity; It is generally comprised within, and specificity combines the part of a class formation or the protein of single native ligand in the live organism; This combination causes acceptor to convert binding signal into another kind of biological agent; For example conduct the signal that has combined to cell, this causes this cell to change its function in some way.The instance of conversion is that the receptors bind of part causes " G-albumen " active change in the endochylema of living cells.The molecule that bind receptor and any naturally occurring or non-natural that makes its activation be used for the signal conversion exist is known as " activator " or " activator ".Bind receptor but do not cause signal conversion combination that take place and that can block activator and molecule that any naturally occurring or non-natural of consequential signal conversion exists is known as " antagonist ".
Like employed term " S1P in this article 1Compound " or " S1P 1Activator " or " S1P 1Activator " or " S1P 1Inhibitor " or " S1P 1Antagonist " refer in some way and S1P receptor subtype 1 interactional compound.They can be activator or activator, and perhaps they can be antagonist or inhibitor." S1P of the present invention 1Compound " can have selectivity to the effect of the hypotype 1 of S1P receptor family; For example, compound of the present invention can with for the lower mass action of other hypotype of S1P receptor family in the hypotype 1 of S1P receptor family; More specifically, with its to hypotype 3 or " S1P 3" effect of acceptor compares " S1P of the present invention 1Compound " can optionally act on hypotype 1 acceptor.
In some embodiments, compound of the present invention is positive structure activator (orthostatic agonist).In some embodiments, compound of the present invention is allosteric activator (allosteric agonist).That receptor stimulating agent can be divided into positive structure or allosteric.Positive structure activator combination combines the site in the obviously overlapping acceptor and duplicates native ligand and the key interactions of acceptor with native ligand.Positive structure activator is competed and is used as competitive ground of the medicament antagonism of the competitive antagonist of native ligand through being similar to the molecular mechanism activated receptor of native ligand with native ligand.The allosteric activator combines the site in generation and the partially or completely nonoverlapping obvious interaction receptor of native ligand.The allosteric activator is real activator, rather than the allosteric reinforcing agent.Therefore, their independent activated receptor signals conduction and do not need the native ligand of time maximum concentration.When known aligning can be confirmed as the allosteric activator when the competitive antagonist of structure part shows noncompetitive antagonism.Allosteric activator site also can be through acceptor mutagenesis location.In acceptor, introduce to keep the receptor activation of allosteric activator and weaken or abolishes single point by the signal conduction (or vice versa) of positive structure agonist induction and suddenly change the form that combines interactional difference evidence is provided.Positive structure activator can make GPCR structure and conformation go to stablize, and the allosteric activator can make GPCR structure and conformation stablize or go to stablize.Because they and the different interaction of acceptor, what the allosteric activator can be for pharmaceutically useful because allosteric site can similarly just provide other possibility for activator potential and selectivity in the relevant family of the receptor subtype of structure part total.In addition, compare with positive structure part, allosteric site possibly need very different activator physics and chemical property.These chemistry-physical propertys (it comprises hydrophobicity, aromaticity, CHARGE DISTRIBUTION and dissolubility) also have to be beneficial to produce and have the activator that characteristic is selected in the different pharmacokineticss, oral administration biaavailability, distribution and the metabolism that help developing active drug.
Like the expression of employed term " basically " in this article fully or almost completely; For example; " do not have " composition of a certain component to represent this component of trace (existence of this trace can not influence any correlation function character of said composition) that this component not comprises basically, perhaps compound for " pure basically " for only there being insignificant trace impurity.
A kind of enantiomer of the pure expression of basic optical is at least 90%, 95%, 98%, 99%, 99.5% or 99.9% about the enantiomer concentration level of another enantiomer.
" treatment " that this paper is alleged or " therapy " refer to the mitigation symptom relevant with disease or illness, or suppress the further progress or the deterioration of those symptoms, perhaps prevent or prevent said illness or disease.
When being used for describing compound of the present invention that compound of the present invention refers at the term " effective dose " when suffering from patient by the disease of 1-phosphoric acid sphingol receptor subtype 1 mediation or illness the purposes of treatment is provided combines individual tissue effectively as activator or as antagonist S1P 1The amount of acceptor, wherein said S1P 1With this disease association, wherein this combination reaches the degree that enough patient is produced useful result of treatment.Similarly; Like what use in this article; " effective dose " of The compounds of this invention or " treatment effective dose " refer to whole or in part and relax and said disease or the relevant symptom of illness; Or stop or slowing down the further progress or the deterioration of those symptoms, the amount that perhaps prevents or prevent the compound of said disease or illness.Particularly, " treatment effective dose " refers to through as 1-phosphoric acid sphingol receptor subtype 1 (S1P 1) active activator plays a role and reach the amount of required treatment results with the dosage of necessity and duration effectively.The treatment effective dose also is the amount that the useful result of treatment of wherein compound of the present invention surpasses any toxicity or illeffects.For example, treating by S1P 1The illness situation of activation mediation under, S1P of the present invention 1The treatment effective dose of activator is to be enough to progress of controlling illness, alleviating illness or the amount of alleviating the symptom of illness.Can be comprised multiple sclerosis, graft rejection, adult respiratory distress syndrome (ARDS) by the instance of the illness of treatment like this.
Can comprise the repulsion of transplant organ or tissue through illness, disease and the illness of compounds for treating of the present invention; The graft versus host disease(GVH disease) that causes by transplanting; Autoimmunity syndrome comprises rheumatoid arthritis; Acute respiratory distress syndrome; Adult respiratory distress syndrome (ARDS); Influenza; Cancer; Systemic loupus erythematosus; Hashimoto thyroiditis; Lymphocytic thyroiditis; Multiple sclerosis; Myasthenia gravis; I type and type ii diabetes; Uveitis; Posterior uveitis; The uveitis relevant with Behcet's disease; Uveomeningitis; Allergic encephalomyelitis; The chronic graft angiosis; Infect the back autoimmunity disease, comprise rheumatic fever and infect the back glomerulonephritis; The inflammatory hyperplasia dermatoses; The epidermis performance of immune-mediated disease; Trichophytosis; Atopic dermatitis; Osteomyelitis; Contact dermatitis; Eczematous dermatitis; Seborrhea; Lichen planus; Pemphigus; Bullous pemphigoid; Epidermolysis bollosa; Nettle rash; Angioedema; Vasculitis; Erythema; The epidermis eosinophilia; Acne; Alopecia areata; Keratoconjunctivitis; Spring conjunctivitis; Keratitis; Herpetic keratitis; Dystrophia epithelialis corneae; Albugo; Ocular pemphigus; Mooren's ulcer; Ulcerative keratitis; Sclerotitis; Ge Leifusishi illness in eye; Vogt-Koyanagi-Harada syndrome; Sarcoidosis; Pollen hypersensitivity symptom; Reversible obstructive airway disease; Bronchial astehma; Allergic asthma; Intrinsic asthma; Extrinsic asthma; Dust asthma; Chronic or long-term asthma; Late-onset asthma and air flue reaction under high pressure; Bronchitis; Stomach ulcer; Ischemic enteropathy; The property intestinal disease; NEC; The intestinal tract injury that thermal burn is relevant; Celiac disease; Rectitis; The eosinophilic gastroenteritis; Mastocytosis; Crohn's disease; Ulcerative colitis; The injury of blood vessel that causes by ischemic disorders and thrombosis; Atherosclerotic; Fatty heart; Myocarditis; Miocardial infarction; Arteriosclerosis; Aortitis syndrome; The cachexia that causes by virus disease; Vascular thrombosis disease; Antimigraine; Rhinitis; Eczema; Interstitial nephritis; The ephrosis that IgA-induces; Goodpasture's syndrome; Hemolytic uremic syndrome; Diabetic nephropathy; Glomerulosclerosis; Glomerulonephritis; Polymyositis; Guillain-Barre syndrome; Plum Ni Ershi is sick; Polyneuritis; Multiple neuritis; Mononeuritis; Radiculopathy; Hyperthyroidism; Basedow's disease; Thyrotoxicosis; Pure red cell aplasia; Alpastic anemia; Hypoplastic anemia; ITP; Autoimmune hemolytic anemia; Agranulocytosis; Pernicious anaemia; Megaloblastic anemia; Red blood cell takes place can not; Osteoporosis; Sarcoidosis; Fibroid lung; Idiopathic interstitial pneumonia; Dermatomyositis; Vitiligo vulgaris is sick; Ichthyosis vulgaris; Photo-allergy is responsive; CTCL; Polyarteritis nodosa; Hungtington's chorea; Sydenham's chorea; Myocardosis; Chorionitis; Granuloma gangraenescens; House Glenn syndrome; Adiposis; Acidophic cell property fascitis; Gums, periodontium, alveolar bone, cemental damage; Male pattern alopecia and alopecia senilis; Muscular dystrophy; Pyoderma; Sai Zeli syndrome; Chronic adrenal insufficiency; Addisonian syndrome; The organ ischemia reperfusion injury that takes place during maintenance; Endotoxin shock; Pseudomembranous colitis; By medicine or radiation-induced colitis; Ischemic acute renal insufficiency; Chronic renal insufficiency; Lung cancer; The malignant tumour in lymph source; Acute or chronic lymphocytic leukemia; Lymphoma; Psoriasis; The inflammatory injury of lungs; Pulmonary emphysema; Cataract; Pneumoconiosis siderotica; Retinal pigment degeneration; Senile macular degeneration; The vitreum scar; Inflammatory eye disease; The corneal alkali burn; The dermatitis erythema; The epidermolysis skin is sick; Cement dermatitis; Gingivitis; Periodontitis; Septicemia; Pancreatitis; Carninomatosis becomes; Metastasis of cancer; Hypobaropathy; Oneself immunity hepatitis; Primary biliary cirrhosis of liver; Sclerosing cholangitis; Liver divides excision; Acute hepatic necrosis; Cirrhosis; Alcoholic cirrhosis; Hepatic failure; FHF; Tardy property hepatic failure; Slow extra urgaent dispatch hepatic failure.The group that comprises following disease with the particularly preferred disease or the illness of compounds for treating of the present invention: the repulsion of transplant organ or tissue; The graft versus host disease(GVH disease) that causes by transplanting; Autoimmunity syndrome comprises rheumatoid arthritis, multiple sclerosis, myasthenia gravis; Pollen hypersensitivity symptom; Type i diabetes; Psoriasic prevention; Crohn's disease; Ulcerative colitis; Acute respiratory distress syndrome; Adult respiratory distress syndrome (ARDS); Influenza; Infect the back autoimmunity disease, comprise rheumatic fever and infect the back glomerulonephritis; And metastasis of cancer.
In addition, formula I-R or I-S compound also can be used to immune system disease, illness and the state relevant and that be selected from above-mentioned tabulation treating and activate with the combination of one or more immunodepressant.According to the preferred embodiment of the present invention, said immunodepressant comprises or by the group of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), imuran (azathiopirene), leflunomide, 15-deoxyspergualin or other immunosuppressive drug for being selected from.
Unless otherwise indicated concrete spatial chemistry or isomeric form, this invention is intended to comprise all chiralitys, diastereomer, racemic form.In the present invention the compound of Shi Yonging can comprise with the enrichment of any degree enrichment or split as in describing conspicuous arbitrarily or the optical isomer of all asymmetric atoms.Can synthesize racemic and mixture diastereomer, thereby and single optical isomer contain their enantiomer or the diastereomer companion body hardly, curse them all in the scope of particular implementation of the present invention.
Because the isomer that the existence of chiral centre causes comprises a pair of isomer that can not be overlapping that is called " enantiomer ".The single enantiomer of pure compound is an optical activity, that is, and and the plane that they can the Plane of rotation polarised light.Single enantiomer is according to the Cahn-Ingold-Prelog systematic naming method.In case the order of priority in four groups confirming then makes molecular orientation so that the group of lowest priority points to the outlying observation person.Then, if to carry out the descending of other group clockwise, then molecule is named as (R) configuration, and if to carry out the descending of other group counterclockwise, then molecule is named as (S) configuration.In this example, the Cahn-Ingold-Prelog preferred order is A＞B＞C＞D.The atom D outlying observation person orientation that said ordering is minimum.
Figure BPA00001577340400241
" optical isomer of separation " refers to the compound of basic purifying from the corresponding optical isomer of same molecular formula.Preferably, it is pure that the isomer of separation is at least about 80 weight %, more preferably pure at least about 90 weight %, even more preferably at least 98 weight % are pure, most preferably pure at least about 99 weight %.
Rotational isomeric
It should be understood that; Because the chemical property of the limited rotation (as follows) that connects around amido link (promptly; Make some two key characteristic give the resonance with the C-N key); Might observe the rotational isomer material of separation; And even isolate such material in some cases, the example is as follows.Should also be understood that some structural element, comprise three-dimensional volume or the substituting group on amide nitrogen, the stability of rotational isomer can be brought up to compound and can be used as the degree that single stable rotational isomer separates and exists chronically.Therefore, the present invention includes any possible stable rotation isomer of compound of the present invention, it is bioactive to it at treatment compound wherein of the present invention as stated in effective disease, illness or the state.
Figure BPA00001577340400251
Position isomerism (Regioisomerism)
The substituent particular space that the preferred compound of the present invention has on aromatic rings is arranged, and it is relevant with the structure-activity relationship that is shown by compound classification.Usually such replacement is arranged and is represented through number system; Yet the number system between different loop systems is normally inconsistent.In the hexatomic ring aroma system, spatial arrangements is specified by trivial nomenclature, and is as follows, " to " expression 1,4 replacement, " " expression 1,3 replaces, and " neighbour " expression 1,2 replaces.
Figure BPA00001577340400252
Contain in the claims all structures for " chemically feasible ", to be the structure that shown by cited optional substituent combination in any of claim or son combination can exist with certain stability at least for confirming through structural chemistry principle and experiment physically its meaning.Chemically infeasible structure is not in the scope of claimed compounds set.
Generally speaking; " substituted " refers in this article the organic group of definition, wherein is included in wherein to be replaced by the one or more key with non-hydrogen atom with one or more keys hydrogen atom, and said non-hydrogen atom for example; But be not limited to halogen (that is, F, Cl, Br and I); Oxygen atom in the group (for example, hydroxyl, alkoxyl, aryloxy group, aralkoxy, oxo (carbonyl), carboxyl comprise: carboxylic acid, carboxylate and carboxylate (carboyxlate esters)); Sulphur atom in the group (for example, sulfydryl, alkyl and aryl thioethers base, sulfoxide group, sulfuryl, sulfonyl and sulfoamido); Nitrogen-atoms in the group (for example amine, azanol, nitrile, nitro, N-oxide, hydrazides, azide and enamine); With other hetero atom in other various groups.The substituent non-limiting instance that can be connected on substituted carbon (or the other) atom comprises: F, Cl, Br, I, OR ', OC (O) N (R ') 2, CN, CF 3, OCF 3, R ', O, S, C (O), S (O), methylene-dioxy, ethylenedioxy, N (R ') 2, SR ', SOR ', SO 2R ', SO 2N (R ') 2, SO 3R ', C (O) R ', C (O) C (O) R ', C (O) CH 2C (O) R ', C (S) R ', C (O) OR ', OC (O) R ', C (O) N (R ') 2, OC (O) N (R ') 2, C (S) N (R ') 2, (CH 2) 0-2NHC (O) R ', (CH 2) 0-2N (R ') N (R ') 2, N (R ') N (R ') C (O) R ', N (R ') N (R ') C (O) OR ', N (R ') N (R ') CON (R ') 2, N (R ') SO 2R ', N (R ') SO 2N (R ') 2, N (R ') C (O) OR ', N (R ') C (O) R ', N (R ') C (S) R ', N (R ') C (O) N (R ') 2, N (R ') C (S) N (R ') 2, N (COR ') COR ', N (OR ') R ', C (=NH) N (R ') 2, C (O) N (OR ') R ' or C (=NOR ') R ', wherein R ' can be for hydrogen or based on carbon based moiety (carbon-based moiety), and wherein said carbon based moiety itself can be by further replacement.
Substituted alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl group and other substituted group also can comprise wherein with one or more key quilts of hydrogen atom and carbon atom or with the substituted group of heteroatomic one or more keys (comprising two keys or triple bond); Said hetero atom includes, but are not limited to the oxygen in carbonyl (oxo), carboxyl, ester, acid amides, acid imide, carbamate (urethane) and the urea groups; With the nitrogen in imines, hydroxyl imide, oxime, hydrazone, amidine, guanidine and the nitrile.The substituting group of substituted group can be further by as defined alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and alkynyl (itself can further be substituted) replace in this article.For example, C 1-4Alkyl can be replaced by amide groups, and amide groups can be further by another C 1-4Alkyl replaces, and it can further be substituted.
The for example substituted aryl of substituted cyclic group, heterocyclic radical and heteroaryl also can comprise wherein substituted ring of key and the fused rings system with the key and the carbon atom of hydrogen.Therefore, substituted aryl, heterocyclic radical and heteroaryl can also quilt as defined alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and alkynyl (itself can further be substituted) replacements in this article.
The term of Shi Yonging " hetero atom " refers to non-carbon and non-hydrogen atom in this article, and it can form covalent bond with carbon, and does not have other restriction.Typical hetero atom is N, O and S.When referring to sulphur (S), only if specialize its state of oxidation, it should be understood that said sulphur can be any state of oxidation of having found, therefore comprise sulfoxide (R-S (O)-R ') and sulfone (R-S (O) 2-R '); Therefore, the sulphur of sulfone form only contained in term " sulfone "; The sulphur of thioether (R-S-R ') form only contained in term " thioether ".When using as during the word of " being selected from the hetero atom of O, NH, NR ' and S " or " [variable] is O, S... ", they should be understood to include the sulphur of all thioethers, sulfoxide and sulfone oxidation state.
Alkyl comprises the straight chain that contains 1 to 20 carbon atom and the alkyl and the cycloalkyl (C of side chain 1-20And typically be and contain 1 to 12 carbon atom (C alkyl), 1-12Alkyl), or in some embodiments, for containing 1 to 8 carbon atom (C 1-8Alkyl), or in some embodiments, for containing 1 to 4 carbon atom (C 1-4Alkyl), or in some embodiments, for containing 1 to 3 carbon atom (C 1-3Alkyl).The instance of straight chained alkyl includes, but are not limited to methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.The instance of branched alkyl includes, but not limited to isopropyl, isobutyl group, sec-butyl, the tert-butyl group, neopentyl, isopentyl and 2,2-dimethyl propyl.Representational substituted alkyl can be replaced one or many by above-mentioned listed any group (for example, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-(thio), alkoxyl and halogen group).Group " primary hydroxyl C 1-4Alkyl " represent by the substituted C of terminal hydroxyl 1-4Alkyl.
Cycloalkyl is for forming the alkyl of ring structure, and it can be substituted or not be substituted.The instance of cycloalkyl includes, but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.In some embodiments, cycloalkyl is 3 to 8 yuan, and in other embodiments, the number of ring carbon atom is 3 to 5,3 to 6 or 3 to 7.Cycloalkyl further comprises the cycloalkyl of many rings, for example, but is not limited to, and norborny, adamantyl, bornyl, camphyl, different camphyl and carene base, and fused rings for example, but are not limited to, decahydro naphthyl (decalinyl) etc.Cycloalkyl also comprises the substituted ring of straight or branched alkyl that is as above defined.Representational substituted cycloalkyl can for example, but be not limited to for mono-substituted or be substituted and surpass once; 2,2-, 2; 3-; 2,4-2,5-or 2; Dibasic cyclohexyl of 6-or list-or two-or three-substituted norborny or suberyl; It can by, for example, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-, alkoxyl and halogen group replace.
It is the ring structure of carbon that term " carbocyclic ring " and " carbocyclic ring " refer to the atom that wherein encircles.In some embodiments, carbocyclic ring is 3 to 8 yuan, and in other embodiments, the number of ring carbon atom is 4,5,6 or 7.Only if make opposite explanation especially, the ring of carbocyclic ring can be by nearly N substituting group (like amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-, alkoxyl and halogen group) replacement, and wherein N is the size of carbocyclic ring.
(cycloalkyl) alkyl is also referred to as cycloalkyl-alkyl, is the hydrogen on the alkyl wherein or carbon bond quilt and the as above substituted as above defined alkyl of key of defined cycloalkyl.
Except existing between two carbon atoms at least one two key, alkenyl comprises the alkyl of as above defined straight chain and side chain and ring-type.Therefore, alkenyl has 2 to about 20 carbon atoms, and 2 to 12 carbon atoms typically, or in some embodiments, 2 to 8 carbon atoms is arranged.The example includes, but not limited to CH=CH (CH 3) ,-CH=C (CH 3) 2,-C (CH 3)=CH 2,-C (CH 3)=CH (CH 3) ,-C (CH 2CH 3)=CH 2, vinyl, cyclohexenyl group, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl etc.
The thiazolinyl of bad shape represented alone or in combination in term " cycloalkenyl group ", wherein in ring structure, has at least one two key.Cycloalkenyl group comprises the cycloalkyl with at least one two key between two adjacent carbon atoms.Therefore, for example, cycloalkenyl group includes, but not limited to cyclohexenyl group, cyclopentenyl and cyclohexadienyl.
(cycloalkenyl group) alkyl is the wherein hydrogen on the alkyl or carbon bond quilt and the as above substituted as above defined alkyl of key of defined cycloalkenyl group.
Except existing at least one triple bond between two carbon atoms, alkynyl comprises the alkyl of straight chain and side chain.Therefore, alkynyl has 2 to about 20 carbon atoms, and 2 to 12 carbon atoms typically, or in some embodiments, 2 to 8 carbon atoms is arranged.The example includes, but are not limited to-C ≡ CH ,-C ≡ C (CH 3) ,-C ≡ C (CH 2CH 3) ,-CH 2C ≡ CH ,-CH 2C ≡ C (CH 3) and-CH 2C ≡ C (CH 2CH 3) etc.
Aryl is not for comprising heteroatomic ring-type aromatic hydrocarbon.Accordingly, aryl groups include, but are not limited to, phenyl, azulene group (azulenyl), heptalenyl (heptalenyl), biphenyl, indacenyl, fluorenyl group, phenanthryl group, phenanthryl benzo (triphenylenyl), pyrene group, naphthalene and naphthyl (naphthacenyl),
Figure BPA00001577340400281
, biphenylene (biphenylenyl), anthryl and naphthyl groups.In some embodiments, aryl comprises 6-14 carbon in artist's loop section of group.Word " aryl " comprises the group that contains fused rings; The fragrance that for example condenses-aliphatic loop systems (for example; Indanyl, tetralyl etc.); And also comprise substituted aryl with other group; Said other group comprises; But be not limited to, be connected to alkyl, halogen, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-or an alkoxyl on the annular atoms.Representational substituted aryl can for example, but be not limited to 2-for single replacement or above once substituted, 3-, and 4-, the substituted phenyl or naphthyl of 5-or 6-, it can be included but not limited to that top listed group replaces.
Aralkyl is hydrogen or the carbon bond quilt of wherein alkyl and the as above substituted as above defined alkyl of key of defined aryl.Representational aralkyl comprises benzyl and phenethyl and (cycloalkyl aryl) alkyl that condenses, like 4-ethyl-indanyl.The two is randomly replaced aryl moiety or moieties or this by other group, includes, but not limited to alkyl, halogen, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-or alkoxyl.Arylalkenyl is the wherein hydrogen on the alkyl or carbon bond quilt and the as above substituted as above defined alkenyl of key of defined aryl.
Heterocyclic radical comprises aromatics or the non-aromatic ring compound (ring of heterocycle) that contains 3 or a plurality of ring memberses, and one or more in the said ring members is hetero atom, for example, but is not limited to N, O, S or P.In some embodiments, heterocyclic radical comprises 3 to 20 ring memberses, and other such group has 3 to 15 ring memberses.At least one ring comprises hetero atom, but needn't comprise hetero atom by each ring in the multi-loop system.For example, the loop systems of dioxolane ring and benzo dioxolanes (methylenedioxyphenyl loop systems) all is the alleged heterocyclic radical of this paper.Called after C 2The heterocyclic radical of-heterocyclic radical can have 2 carbon atoms and 4 heteroatomic 6 yuan of rings or the like for having 2 carbon atoms and 3 heteroatomic 5 yuan of rings.Same, C 4-heterocyclic radical can have 2 first rings of heteroatomic 6-or the like for having 1 first ring of heteroatomic 5-.The number of carbon atom adds that the summation of heteroatomic number equals the sum of annular atoms.Saturated heterocycle refers to the heterocycle that does not comprise unsaturated carbon atom.
Word " heterocyclic radical " comprises that containing those has the aromatics that condenses and the fused rings kind of non-aromatic group.This word also comprises and contains heteroatomic many ring loop systems; Such as but not limited to quininuclidinyl (quinuclidyl); And also comprise and have substituent heterocyclic radical; Said substituting group comprises; But be not limited to, be connected to alkyl, halogen, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-or an alkoxyl on the ring members.Can or comprise the partially or completely saturated cyclic group of at least one ring hetero atom for heteroaryl like heterocyclic radical defined herein.The heterocyclic radical group comprises; But be not limited to pyrrolidinyl; Furyl; Tetrahydrofuran base; Dioxolanyl; Piperidyl; Piperazinyl; Morpholinyl; Pyrrole radicals; Pyrazolyl; Triazolyl; Tetrazole radical oxazolyl isoxazolyl; Thiazolyl; Pyridine radicals; Thienyl; Benzothienyl; Benzofuranyl; Dihydro benzo furyl; Indyl; Indolinyl; Azaindolyl; Indazolyl; Benzimidazolyl; Azepine benzimidazolyl; benzoxazolyl; Benzothiazolyl; Diazosulfide; Imidazopyridyl isoxazole and pyridine radicals; Thia naphthyl (thianaphthalenyl); Purine radicals; Xanthinyl; Adenyl; Guanyl-; Quinolyl; Isoquinolyl; Tetrahydric quinoline group quinoxalinyl and quinazolyl group.Heterocyclic radical can be substituted.Representational substituted heterocyclic radical can be for mono-substituted or surpass once substituted; Include but not limited to; Wherein by above-named substituting group list, two, three, four, five, six or more times substituted at least one heteroatomic ring that comprises; Said substituting group comprises; But be not limited to alkyl, halogen, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-and alkoxyl.
Heteroaryl is the aromatic ring compound that comprises 5 above annular atomses, and wherein, at least one annular atoms is a hetero atom, for example, but is not limited to N, O and S.Called after C 2The heteroaryl of heteroaryl can have 2 carbon atoms and 4 heteroatomic 6 yuan of rings or the like for having 2 carbon atoms and 3 heteroatomic 5 yuan of rings.Same, C 4-heteroaryl can have 2 first rings of heteroatomic 6-or the like for having 1 first ring of heteroatomic 5-.The number of carbon atom adds that the summation of heteroatomic number equals the sum of annular atoms.Heteroaryl groups comprises; But be not limited to; For example, pyrrole radicals; Pyrazolyl; Triazolyl; Tetrazole radical oxazolyl isoxazolyl; Thiazolyl; Pyridine radicals; Thienyl; Benzothienyl; Benzofuranyl; Indyl; Azaindolyl; Indazolyl; Benzimidazolyl; Azepine benzimidazolyl; benzoxazolyl; Benzothiazolyl; Diazosulfide; Imidazopyridyl isoxazole and pyridine radicals; Thia naphthyl (thianaphthalenyl); Purine radicals; Xanthinyl; Adenyl; Guanyl-; Quinolyl; Isoquinolyl; Tetrahydric quinoline group; Tetrahydro isoquinolyl quinoxalinyl and quinazolyl group.Term " heteroaryl " and " heteroaryl groups " comprise the fused rings compound, and for example, at least one ring wherein, but all rings not necessarily are aromatic ring, comprise tetrahydric quinoline group, tetrahydro isoquinolyl, indyl and 2, the 3-indolinyl.Said term comprises also and contains the heteroaryl that is connected to other group on one of annular atoms that said other group includes, but not limited to alkyl, halogen, amino, hydroxyl, cyanic acid, carboxyl, nitro, sulfo-or alkoxy base.Representational substituted heteroaryl groups can be replaced one or many by for example above-named those groups.
Aryl and heteroaryl additional examples include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1 - naphthyl, 2 - naphthyl), N-hydroxy-tetrazolyl, N-hydroxyltrimethylammonium oxazolyl, N-hydroxy-imidazolyl group, an anthryl group (1 - anthryl group, a 2 - anthryl group, a 3 - anthryl group), thienyl group (2 - thienyl group, a 3 - thienyl), furyl group (2 - furyl group, 3 - furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl group, xanthene group, an iso-indanyl (isoindanyl), benzhydryl, acridinyl, thiazolyl, group, a pyrrolyl group (2 - pyrrolyl), pyrazolyl (3 - pyrazolyl), imidazolyl group (1 - imidazolyl, 2 - imidazolyl group, 4 - imidazolyl, 5 - imidazolyl), triazolyl ( 1,2,3 - triazol-1 - yl, 1,2,3 - triazol-2 - yl, 1,2,3 - triazol-4 - yl, 1,2,4 - triazol-3 - group), oxazolyl group (2 - oxazolyl group, 4 - oxazolyl, 5 - oxazolyl), thiazolyl group (2 - thiazolyl group, a 4 - thiazolyl, 5 - thiazolyl), pyridyl group (2 - pyridyl, 3 - pyridyl, 4 - pyridyl), pyrimidinyl group (2 - pyrimidinyl group, a 4 - pyrimidinyl group, a 5 - pyrimidinyl, 6 - pyrimidinyl), pyrazinyl, pyridazinyl (3 - pyridazinyl yl, 4 - pyridazinyl, 5 - pyridazinyl), quinolyl group (2 - quinolyl group, 3 - quinolyl group, 4 - quinolyl, 5 - quinolyl, 6 - quinolyl, 7 - quinolyl 8 - quinolyl), isoquinolinyl (1 - isoquinoline group, 3 - isoquinolyl 4 - isoquinoline group, a 5 - isoquinolyl 6 - isoquinoline yl, 7 - isoquinolyl 8 - isoquinolyl), benzo [b] furanyl (2 - benzo [b] furyl group, 3 - benzo [b] furyl group, 4 - benzo [ b] furanyl, 5 - benzo [b] furanyl, 6 - benzo [b] furan-yl, 7 - benzo [b] furanyl), 2,3 - dihydro - benzo [b] furanyl (2 - (2,3 - dihydro - benzo [b] furanyl), 3 - (2,3 - dihydro - benzo [b] furanyl), 4 - (2,3 - dihydro - benzene and [b] furanyl), 5 - (2,3 - dihydro - benzo [b] furanyl), 6 - (2,3 - dihydro - benzo [b] furanyl), 7 - (2 3 - dihydro - benzo [b] furanyl)), benzo [b] thienyl group (2 - benzo [b] thienyl group, 3 - benzo [b] thienyl group, a 4 - benzo [b ] thienyl, 5 - benzo [b] thienyl, 6 - benzo [b] thiophen-yl, 7 - benzo [b] thienyl), 2,3 - dihydro - benzo [b] thienyl (2 - (2,3 - dihydro - benzo [b] thienyl), 3 - (2,3 - dihydro - benzo [b] thienyl), 4 - (2,3 - dihydro - benzene and [b] thienyl), 5 - (2,3 - dihydro - benzo [b] thienyl), 6 - (2,3 - dihydro - benzo [b] thienyl), 7 - (2 3 - dihydro - benzo [b] thienyl)), indolyl group (1 - indolyl group, a 2 - indolyl group, a 3 - indolyl group, a 4 - indolyl, 5 - indolyl, 6 - indolyl 7 - indolyl), indazole (1 - indazolyl group, a 3 - indazolyl group, a 4 - indazolyl, 5 - indazolyl, 6 - indazolyl 7 - indazole yl), benzimidazolyl group (1 - benzimidazolyl group, 2 - benzimidazolyl group, 4 - benzimidazolyl, 5 - benzimidazolyl, 6 - benzimidazolyl 7 - benzimidazolyl, 8 - benzimidazolyl), benzoxazolyl (1 - benzoxazolyl group, a 2 - benzoxazolyl), benzothiazolyl (1 - benzothiazolyl group, a 2 - benzothiazolyl 4 - benzothiazolyl, 5 - benzothiazolyl, 6 - benzothiazolyl 7 - benzothiazolyl), carbazolyl (1 - carbazolyl group, a 2 - carbazolyl group, a 3 - carbazole yl, 4 - carbazolyl), 5H-dibenz [b, f] azepine
Figure BPA00001577340400311
base (5H-dibenzo [b, f] azepine
Figure BPA00001577340400312
-1 - yl, 5H-dibenzo [b, f] aza
Figure BPA00001577340400313
-2 - yl, 5H-dibenzo [b, f] azepine -3 - yl, 5H-dibenzo [b, f] azepine
Figure BPA00001577340400315
-4 - yl, 5H-dibenzo [b, f ] aza
Figure BPA00001577340400316
-5 - yl), 10,11 - dihydro-5H-dibenz [b, f] azepine
Figure BPA00001577340400317
(10,11 - dihydro-5H-dibenzo [b, f] azepine
Figure BPA00001577340400318
-1 - yl, 10,11 - dihydro-5H-dibenz [b, f] azepine
Figure BPA00001577340400319
-2 - yl, 10,11 - dihydro-5H-dibenzo [b, f] azepine -3 - yl , 10,11 - dihydro-5H-dibenzo [b, f] azepine
Figure BPA000015773404003111
-4 - yl, 10,11 - dihydro-5H-dibenzo [b, f] azepine
Figure BPA000015773404003112
-5 - yl) etc. .
The heterocyclic radical alkyl group is hydrogen or the carbon bond quilt of wherein alkyl and the as above substituted as above defined alkyl of key of defined heterocyclic radical.Representational heterocyclic radical alkyl includes, but are not limited to furans-2-ylmethyl, furans-3-ylmethyl, pyridine-2-ylmethyl (α-picolyl), pyridin-3-yl methyl (β-picolyl), pyridin-4-yl methyl (γ-picolyl), oxolane-2-base ethyl and indoles-2-base propyl group.The heterocyclic radical alkyl group can perhaps be substituted on both at heterocyclic radical part, moieties.
Heteroaryl alkyl is the wherein hydrogen on the alkyl or carbon bond quilt and the as above substituted as above defined alkyl of key of defined heteroaryl.The heteroaryl alkyl group can perhaps be substituted on both at heteroaryl moieties, moieties.
The part that comprises 1,2,3 or more a plurality of rings like term " loop systems " expression of using in this article; It can replace by non-cyclic group or by other loop systems or by both; It can for fully saturated, part is undersaturated, fully undersaturated or aromatics; And when said loop systems comprised the loop systems more than single ring, said ring can be for that condense, bridge joint or volution.As well known in the art, " volution " expression is two class formations that ring condenses on single quaternary carbon atom (tetrahedral carbon atom) wherein,
Employed in this article term " fragrance or the part aromatic rings of monocycle, dicyclo or many rings " refers to and comprises the perhaps loop systems of (hydrogenation) form of its partial reduction of unsaturated ring with 4n+2 pi-electron.The ring of said fragrance or part fragrance can comprise and extra itself is not fused rings aromatics or partially aromatic, bridge joint ring or volution.For example, naphthalene and naphthane all are this paper alleged " aromatic rings or the part aromatic rings of monocycle, dicyclo or many rings ".In addition, for example, benzo-[2.2.2]-double-octane also is this paper alleged " aromatic rings or the part aromatic rings of monocycle, dicyclo or many rings ", comprises the phenyl ring that the bicyclic system with bridging condenses.Fully saturated ring does not wherein have two keys, and whether is carbocyclic ring or heterocycle according to the sub existence of the alleged heterocycle of this paper.
As above defined, term " alkoxyl " refers to the oxygen atom that is connected on the alkyl group (comprising cycloalkyl).The instance of straight chain alkoxyl includes, but not limited to methoxyl group, ethyoxyl, positive propoxy, n-butoxy, n-pentyloxy, just own oxygen base etc.The instance of branched alkoxy includes, but not limited to isopropoxy, the second month in a season-butoxy, tert-butoxy, isoamoxy, dissident's oxygen base etc.The instance of cycloalkyloxy includes, but not limited to encircle propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Term " aryloxy group " and " alkoxy aryl " refer to the aryl that is connected on the oxygen atom respectively and are connected to the aryl alkyl on the oxygen atom at moieties.The example includes but not limited to phenoxy group, naphthoxy and benzyloxy.
Refer to the group that comprises carbonyl moiety like employed term " acyl group " in this article, wherein this group is through the carbonylic carbon atom bonding.Said carbonylic carbon atom is another carbon atom of bonding also, and it can be the part of alkyl, aryl, aralkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl group etc.Said therein carbonyl is connected in the particular case on the hydrogen, and this group is " formoxyl ", and it is as the acyl group of defined term in this article.Acyl group can comprise and is connected to 0 on the carbonyl group to about 12-20 extra carbon atom.The alleged acyl group of this paper can comprise two keys or triple bond.Acryloyl group is the instance of acyl group.The alleged acyl group of this paper also can comprise hetero atom.Nicotinoyl base (pyridine radicals-3-carbonyl) is the instance of the alleged acyl group of this paper.Other instance comprises acetyl group, benzoyl, phenylacetyl group, pyridine acetyl group, cinnamoyl and acryloyl group etc.Comprise halogen when plain when comprising the group that is connected to the carbon atom on the carbonylic carbon atom, this group is called " halo acyl group " group.Instance is a trifluoroacetyl group.
Term " amine " comprises having formula N (group) 3Primary, the second month in a season and tertiary amine, wherein each group can be H or non-hydrogen, for example alkyl, aryl etc. independently.Amine includes, but not limited to RNH 2, for example, alkylamine, arylamine, alkylarylamine; R 2NH, wherein each R independently selects, for example, dialkylamine, diaryl amine, aralkylamine, heterocyclic radical amine etc.; And R 3N, wherein each R selects independently, for example trialkylamine, di alkylaryl amine, alkyl diaryl amine, triarylamine etc.Term " amine " also comprises the ammonium ion that uses as in this article.
" amino " is-NH 2,-NHR ,-NR 2,-NR 3 +The substituting group of form (wherein each R selects independently) and its each protonated form.Therefore, can be considered as amine by amino substituted any compound.
" ammonium " ion comprises unsubstituted ammonium ion NH 4 +Only if, but point out that in addition it also comprises any protonated or quaternised form of amine.Therefore, Trimethylamine hydrochloride and tetramethyl ammonium chloride are alleged ammonium ion of this paper and amine simultaneously.
Term " acid amides " (or " acylamino-") comprises C-and N-amide group respectively, promptly-C (O) N R ' R " with-NR ' C (O) R " group.The R ' of C-acid amides and R " can be combined together to form the heterocycle with nitrogen-atoms.Therefore, its amide groups includes, but not limited to carbamoyl (C (O) NH 2) and carbonylamino group (NHC (O) H)." acid amides (carboxamido) " group is general formula C (O) NR 2Group, wherein, R can be H, alkyl, aryl etc.
Term " carbamate (urethane) " (or " carbamoyl ") comprises N-and O-carbamate groups respectively, that is, and and-NRC (O) OR and-OC (O) NR 2Group.
Term " sulfonamide " (or " sulfonamido (sulfonamido) ") comprises S-and N-sulfoamido respectively, promptly-and SO 2NR 2With-NRSO 2The R group.Therefore, sulfuryl amine group includes, but not limited to sulfamoyl group (SO 2NH 2).
Term " amidine (amidine) " or " amidino groups (amidino) " comprise formula-C (NR) NR 2Group.Usually, amidino groups is-C (NH) NH 2
Term " guanidine (guanidine) " or " guanidine radicals (guanidino) " comprise formula-NRC (NR) NR 2Group.Usually, guanidine radicals is-NHC (NH) NH 2
" halo ", " halogen " and " halide " comprise fluorine, chlorine, bromine and iodine.
In this article the term of Shi Yonging " comprise ", " comprising ", " containing ", " having " and " by ... form " be open-ended term, and do not get rid of the extra composition or the existence of component.In alleged composition; Use " comprising ", " comprising ", " containing ", " having " or " by ... form " what composition expression no matter comprise, comprise, contain, have or form, it must not be the unique composition that comprises that the theme of the sentence of this speech is contained.
As known in the field, " salt " includes organic compounds, for example, and with carboxylic acid, sulfonic acid or the amine of ionic species and counter ion counterionsl gegenions combination.For example, the acid of its anionic form can with cation for example, metal cation is like sodium, potassium etc.; With ammonium salt, like NH 4 +Or the cation of various amine, comprise tetraalkylammonium salt such as tetramethyl-ammonium and alkylammonium salt such as amino butanetriol salt; Or other cation, like formation salt such as trimethyl sulphur." pharmaceutically acceptable " or " acceptable on the pharmacology " salt is by ratifying to be used for the human consumption's and the salt that forms of normally nontoxic ion, for example, and villaumite or sodium salt." amphion " is inner salt, for example the inner salt that can in the molecule with at least two ionizable groups (one forms anion and another formation cation, and it is used to balance each other), form.For example, amino acid (like glycine) can exist with zwitterionic form." amphion " belongs to the alleged salt of this paper.Compound of the present invention can be taked the form of salt.Term " salt " comprises as the free acid of compound of the present invention or the addition salts of free alkali.Salt can be " pharmaceutically acceptable salt ".Term " pharmaceutically acceptable salt " refers to the salt that the toxicity characteristic in the effectiveness scope in the medicinal application is provided.But pharmaceutically unacceptable salt can have the for example performance of high-crystallinity, and it has effectiveness in enforcement of the present invention, for example, and as in synthetic, the purifying of compound of the present invention or the effectiveness in the process for preparation.
Suitable pharmaceutically-acceptable acid addition can be by inorganic acid or organic acid preparation.Representative examples of mineral pigments comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Appropriate organic can be selected from aliphatic; Alicyclic; Aromatics; Araliphatic (araliphatic); Heterocycle; The organic acid of carboxylic acid and sulfonic acid class; The example comprises, formic acid; Acetate; Propionic acid; Succinic acid; Glycolic acid; Gluconic acid; Lactic acid; Malic acid; Tartaric acid; Citric acid; Ascorbic acid; Glucuronic acid; Maleic acid; Fumaric acid; Pyruvic acid; Asparatate; Glutamic acid; Benzoic acid; Ortho-aminobenzoic acid; The 4-hydroxybenzoic acid; Phenylacetic acid; Mandelic acid; Methylene pamoic acid (pouncing on acid); Methanesulfonic acid; Ethyl sulfonic acid; Benzene sulfonic acid; Pantothenic acid; Trifluoromethanesulfonic acid; The 2-ethylenehydrinsulfonic acid; P-methyl benzenesulfonic acid; Sulfanilic acid; The cyclohexyl sulfamic acid; Stearic acid; Alginic acid; Beta-hydroxy-butanoic acid; Salicylic acid; Galactosaccharic acid and galacturonic acid.Pharmaceutically the instance of unacceptable acid-addition salts comprises, for example, and perchlorate and tetrafluoroborate.
The suitable pharmaceutically acceptable base addition salts of compound of the present invention comprises that for example, slaine comprises alkali metal salt, alkali salt and transition metal salt, for example, and like calcium salt, magnesium salts, sylvite, sodium salt and zinc salt.Pharmaceutically acceptable base addition salts also comprises the organic salt by the basic amine preparation, for example, like N, N '-dibenzyl-ethylenediamin, chloroprocanine, choline, diethanol amine, ethylenediamine, meglumine (N-methyl glucoside amine) and procaine.Pharmaceutically the instance of unacceptable base addition salts comprises lithium salts and cyanate.Although not as medicine, such salt can be used as pharmaceutically unacceptable salt usually, for example, the intermediate in the synthetic process of compound, for example, in its purge process through recrystallization.All these salt can be through for example making, and suitable acid or alkali and corresponding compounds reaction and conventional mode are by this compound.Term " pharmaceutically acceptable salt " refers to nontoxic inorganic or organic acid and/or base addition salts, referring to people such as for example Lit, Salt Selection for Basic Drugs (1986); Int J.Pharm.; 33,201-217, its mode by reference is incorporated among this paper.
The limiting examples of potential salt of the present invention comprises; But be not limited to hydrochloride; Citrate; Oxyacetate; Fumarate; Malate; Tartrate; Mesylate; Esilate; Cinnamate; Isethionate; Sulphate; Phosphate; Hydrophosphate; Nitrate; Hydrobromate; Hydriodate; Succinate; Formates; Acetate; DCA; Lactate; Tosilate; Palmitate; Pyrrone hydrochlorate (pidolate); Pamoate; Salicylate; The 4-aminosalicylate; Benzoate; 4-acetaminobenzoic acid salt; Glutamate; Aspartate; Oxyacetate; Adipate; Alginates; Ascorbate; Benzene sulfonate; Camphorate; Camsilate; D-camphorsulfonic acid salt; Caprate; Caproate; Cyclamate; Lauryl sulfate; Ethanedisulphonate; Gentisate; Mutate; Gluceptate; Gluconate; Glucuronate salt; Ketoglutarate; Hippurate; Lactobionate; Malonate; Maleate; Mandelate; Naphthalene sulfonate; Napadisilate; Oxalate; Oleate; Sebacate; Stearate; Succinate; Rhodanate; Undecylenate and xinafoate.
" hydrate " is the compound that exists with the composition with hydrone.Said composition can comprise the water of stoichiometric amount, and for example monohydrate or dihydrate perhaps can comprise the water of any amount.The term of Shi Yonging " hydrate " refers to solid form in this article, that is, though the compound in the aqueous solution can be for hydration, it is not the hydrate like the term that uses in this article.
" homologue " of compound of the present invention is the compound that one or more atoms of this compound are substituted by the isotope of this atom.For example, homologue comprises the compound with some hydrogen atoms in the deuterium substituted compound, and for example, the methyl of the isopropyl of its Chinese style I-R and I-S part is all or part of by deuterate (for example, (D 3C) 2C-O-) compound of the present invention.The isotope that in the formation of homologue of the present invention, can carry out replaces and comprises inactive (stable) atom, for example, and deuterium and carbon 13, and radioactive (unsettled) atom, for example, tritium, carbon 14, iodine 123, iodine 125 etc.
Solvent except making water replaces outside the water, and " solvate " is similar compositions.For example, methyl alcohol or ethanol can form " alcoholates ", and it also can be stoichiometry or non-stoichiometric.The term of Shi Yonging " solvate " refers to solid form in this article, that is, though the compound in the solution of solvent is a solvation, it is not the solvate like the term that uses in this article.
As known in the field, " prodrug " is the material that can use to the patient, and wherein this material is converted into active drug ingedient through the effect of the biochemical (for example, enzyme) in patient's body in vivo.The instance of prodrug comprises the ester of hydroxy-acid group, and it can be hydrolyzed through endogenous esterase (like what in human and other mammiferous blood, find).
Can be used as prodrug through any compound that chemistry or biochemical translation function are converted into active medicine in vivo plays a role.The prodrug of said compound has been contained in the present invention.
Some instances of prodrug within the scope of the present invention comprise:
If i. compound comprises hydroxyl, then this hydroxyl can be modified to form ester, carbonic ester or carbamate.The example comprises acetic acid esters, pivalate, methyl and ethyl carbonate ester and dimethylcarbamate.This ester can also be by amino acid, and for example glycine, serine or lysine are derived.
If ii. compound comprises amido, then this amido can be modified to form acid amides.The example comprise acetamide or with the derivative of amino acid (for example, glycine, serine or lysine).
Some compound of the present invention and their salt can exist to surpass a kind of crystal formation, and the present invention includes each crystal formation and composition thereof.In addition, compound of the present invention can with non-solventization and with pharmaceutically acceptable solvent (for example water) solvation with form hydrate or with alcohol (like C 1-4The form of addition product-alkanol) etc. exists.In addition, compound of the present invention can associate with solvent molecule through the evaporative crystallization from suitable solvent and separate.Such solvent comprises; But be not limited to, toluene, oxolane 、 diox, dimethyl formamide, acetonitrile, acetic acid esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, propyl acetate and isopropyl ester, ether such as diethyl ether and ethyl ether, alcohol are like methyl alcohol, ethanol, 1-or 2-butanols, 1-or 2-propyl alcohol, amylalcohol and methyl-sulfoxide.Generally speaking, describe compound through structure or title and be considered to comprise any type of this compound (for example, compound itself, hydrate, solvate, or other form of mixture).
In addition, characteristic of the present invention and aspect are through the formal description of Ma Kushi group, and those of ordinary skill in the art will recognize that therefore the present invention is to describe through any single member of Ma Kushi group or member's Asia group also.For example, be selected from bromine, chlorine and iodine if X is described as, then having described X fully is that bromine and X are the claim of chlorine and iodine.In addition, characteristic of the present invention and aspect under the situation of formal description through the Ma Kushi group, the those skilled in the art of this area will recognize that therefore the present invention also is that any single member's through the Ma Kushi group combination or member's Asia group are described.Therefore, for example, if X is described as and is selected from bromine, chlorine and iodine and Y and is described as and is selected from methyl, ethyl and propyl group, then having described X fully is that bromine and Y are the claim of methyl.
Composition and therapeutic alliance
S1P of the present invention 1Compound, their pharmaceutically acceptable salt or hydrolyzable ester can combine with pharmaceutically acceptable carrier with the biological disease of mentioning in this article that is provided for treating mammalian species (and more preferably people) or the pharmaceutical composition of illness.The specific support that in these pharmaceutical compositions, uses can be used type (for example, vein, per os, part, suppository or parenteral) and changes according to required.
(for example, suspension, elixir or solution in) the composition, can adopt typical medicinal medium, for example water, glycols, oil, alcohol, flavor enhancement, preservative, colouring agent etc. in preparation liquid oral formulation.Similarly, when preparation oral dosage form (for example, powder, sheet or capsule), can adopt carrier such as starch, sugar, thinner, granulating agent, lubricant, adhesive, disintegrant etc.
Embodiment of the present invention provide on the other hand compound of the present invention individually or with another S1P 1The composition of inhibitor or another kind of therapeutic agent or this two combination.As described in this article, compound of the present invention comprises stereoisomer, dynamic isomer, solvate, hydrate, salt (comprising pharmaceutically acceptable salt) and composition thereof.Comprising compound compositions of the present invention can be through conventional technology preparation, for example, as described in the following document: Remington, The Science and Practice of Pharmacy, 19th Ed., 1995, it incorporates this paper by reference into.Said composition can appear with the form of routine, for example, and capsule, tablet, aerosol, solution, suspension or topical application form.
Typical composition comprises compound of the present invention and pharmaceutically acceptable excipient, and this excipient can be carrier or thinner.For example, reactive compound mixes with carrier usually, and perhaps suppressed by vector dilution perhaps is encapsulated in the carrier (it can be ampoule, capsule, flat capsule, paper or other packing material).When reactive compound mixed with carrier, perhaps time spent of doing of playing thinner when carrier, it can be solid-state, the semisolid or the liquid of the effect of the media, excipient or the medium that play reactive compound.Reactive compound can be adsorbed on the granular solid-state carrier, for example, is included in the flat capsule.Some instances of suitable carriers are water; Salting liquid; Alcohol; Polyethylene glycol; The castor oil of polyhydroxy ethoxylation (polyhydroxyethoxylated castor oil); Peanut oil; Olive oil; Gelatin; Lactose; Land plaster; Sucrose; Dextrin; Magnesium carbonate; Sugar; Cyclodextrin; Amylose; Dolomol; Talcum powder; Gelatin; Agar; Pectin; Gum Arabic; Stearic acid or cellulosic lower alkyl ether; Silicic acid; Fatty acid; Fatty acid amine (fatty acid amine); Glycerine monofatty ester; Fatty acid two glyceride; Fatty acid pentaerythritol ester; Polyethylene glycol oxide; CMC and polyvinylpyrrolidone.Similarly, carrier or thinner can comprise any slow-release material as known in the art, for example, and glycerin monostearate or distearin independent or that mix with wax.
Preparation can with can sharply mix with the auxiliary agent that reactive compound reacts.Such additive can comprise wetting agent, emulsifier and suspending agent, influence the salt of osmotic pressure, buffer and/or coloring material, preservative, sweetener or flavor enhancement.If desired, said composition can also be sterilized.
The approach of administration can be transported to any approach of suitable or required action site for the reactive compound of the present invention of the enzymic activity that will suppress focal adhesion kinase effectively; For example; Per os, intranasal, lung, suck, subcutaneous, intracutaneous, through skin or parenteral; As in rectum, bank, subcutaneous, intravenous, the urethra, in the intramuscular, nose, ophthalmic solution or ointment, preferred per os approach.
As for parenteral, carrier generally includes sterile water, although also can comprise other composition hydrotropy or that play the preservative effect.In addition, injectable suspension can also be prepared, in this case, suitable liquid-carrier, suspending agent etc. can be adopted.
As for topical, can use matrix (for example ointment or emulsifiable paste) gentle, that preserve moisture to prepare compound of the present invention.
If solid-state carrier is used to oral administration, preparation can be made into sheet, inserts in the hard gelatin capsule with powder shape or piller form, and perhaps it can be the form of lozenge or dragee.If the use liquid carrier, preparation can be the form of syrup, emulsion, Perle or aseptic parenteral solution (for example, water-based or non-aqueous liquid suspension or solution).
Injectable dosage formulations generally comprises waterborne suspension or oil suspension, and it can use suitable dispersant or wetting agent and suspending agent preparation.Injectable dosage formulations can be the solution phase of use solvent or thinner preparation or the form of suspension.Acceptable solvent or media comprise sterile water, ringer's solution or etc. the saline solution that oozes.Perhaps, can use aseptic oil as solvent or suspending agent.Preferably, oil or fatty acid are nonvolatile, comprise natural or synthetic oil, fatty acid, list-, two-or Three-glycerol ester.
For injection, preparation can also be for being fit to the powder with aforesaid suitable solution reconstruct.Their instance includes, but not limited to cryodesiccated, Rotary drying or spray-dired powder, amorphous powder, particle, sediment or particulate matter.For injection, preparation can randomly comprise stabilizing agent, pH regulator agent, surfactant, bioavailability conditioning agent and combination thereof.These compounds can be used for the parenteral through injection (for example through injecting fast or continuous infusion) by preparation.The unit dosage form that is used for injecting can be at ampoule bottle or in multi-dose container.
The quick, lasting of active component is provided after using to the patient or postpones release through utilizing method well known in the art preparation of the present invention can be designed to.Therefore, said preparation can also be mixed with and be used for sustained release or be used for slow release.
The composition that the present invention includes can comprise, for example, micella or liposome, perhaps some other encapsulated form perhaps can be used long term storage to be provided and/or to send effect to prolong release dosage form.Therefore, said preparation can be pressed into granule or cylinder, and as in the bank injection muscle or subcutaneous implantation.Such implant can adopt known inert material such as polysiloxanes and Biodegradable polymeric, for example, and polylactide-gather glycolide.The instance of other Biodegradable polymeric comprises and gathers (ortho esters) and gather (acid anhydrides).
For nose administration, preparation can comprise the compound of the present invention of the enzymic activity that suppresses focal adhesion kinase, and it is dissolved or suspended in the liquid-carrier (preferred aqueous carrier) and is used for aerosol applications.Carrier can comprise additive, for example solubilizer (like propane diols), surfactant, sorbefacient (like lecithin (phosphatid ylcholine) or cyclodextrin) or preservative (like parabens).
For parenteral application, particularly suitable is injection solution or suspension, preferably has the aqueous solution that is dissolved in the reactive compound in the polyhydroxylated castor oil.
Can be by sky or one day (for example every day twice or three times) form of administration repeatedly.Perhaps, if the suggestion that the prescriber provides, can be to be less than lower frequency form of administration once a day, for example, per two days are once, or weekly.
Embodiment of the present invention also comprises the prodrug of The compounds of this invention, and it experienced chemical conversion through metabolism or other physiology course before becoming pharmacological active substance after administration.Conversion through metabolism or other physiology course includes, but not limited to prodrug is converted into (for example, general or specific acid or alkali are induced) chemical conversion of zymetology (for example, specific enzymatic) and the non-zymetology of pharmacological active substance.Generally speaking, such prodrug is a compound functions property derivative of the present invention, and it easily is converted into compound of the present invention in vivo.The conventional method of selecting and preparing suitable prodrug derivant is documented in the following document: for example, and Design of Prodrugs (design of prodrug), ed.H.Bundgaard, Elsevier, 1985.
In another embodiment, the method for preparing compound compositions as herein described is provided, has comprised compound of the present invention is prepared with pharmaceutically acceptable carrier or thinner.In some embodiments, pharmaceutically acceptable carrier or thinner are suitable for oral administration.In some embodiments, said method can also comprise the step that said composition is mixed with tablet or capsule.In other embodiments, said pharmaceutically acceptable carrier or thinner are suitable for parenteral.In some embodiments, said method further comprises said composition freeze-drying to form the step of lyophilized formulations.
Compound of the present invention can be used for therapeutic purposes with following material: i) one or more other S1P 1Inhibitor and/or the ii) kinases inhibitor of one or more other types and/or the therapeutic agent of one or more other types; It can be with identical formulation oral administration, (for example use with independent peroral dosage form; Sequentially or sequentially non-) or use (for example, order or sequentially non-) through injection separately or together.
Therefore, the present invention provides combination in another embodiment, and it comprises:
A) like described compound of the present invention in this article; With
B) one or more compounds, it comprises:
I) other compound of the present invention;
Ii) be fit to needs S1P in the treatment medical treatment 1The other medicines of the illness (for example, multiple sclerosis, graft rejection or adult respiratory distress syndrome (ARDS)) that activates.
Combination of the present invention comprise with the mixture of (a) of single preparation and the compound of (b) with as (a) that separate preparation and compound (b).The preparation packing that combinations more of the present invention can be used as separation is in kit.In some embodiments, two or more compounds in (b) are prepared together, and compound of the present invention is prepared individually.
Under suitable situation, the dosage and the preparation of the other medicines that can as the Physicians ' Desk Reference (doctor's medicine guide) of latest edition is described, use, the document is incorporated this paper by reference into.
Methods of treatment
In some embodiments, the present invention includes exciting specifically S1P 1And do not combine other EDG acceptor (S1P 2, S1P 3And S1P 4) or other EDG acceptor is had significant specificity (S1P 5) the compound of orally-ingestible biological utilisation (orally bioavailable).Can use optionally S1P 1Activator treat have autoimmunity, excessively immune response, blood vessel take place or the disease of inflammation composition, but be not limited to these illness.Compare with the present therapy of treating window through raising, optionally S1P 1Activator has advantage, because reduced owing to involve the toxicity that other EDG acceptor causes.
In some embodiments, the present invention includes with the main formula high-affinity of activator with combine S1P with high specificity 1The compound of acceptor.At S1P 1When acceptor engages with activator, signal conduction passing through G α iCarry out, thereby the cAMP that suppresses adenyl cyclase produces.
In some embodiments, the invention provides and use compound of the present invention to activate or excited (that is, have excited effect (agonic effect), play the effect of activator) 1-phosphoric acid sphingol receptor subtype (S1P for example 1) method.Said method comprises makes acceptor contact to cause the activation of acceptor with the compound of the present invention of suitable concn.Said contact can occur in external, for example, thereby in analyzing experiment, carries out submitting the relevant experiment of application for registration to the active completion of the S1P receptor activation of measuring compound of the present invention.
In some embodiments, activate S1P acceptor (S1P for example 1) method also can implement in vivo, that is, and in vivo mammiferous, the animal of human patients or test for example.Compound of the present invention can offer live organism through one of aforesaid approach (for example per os), perhaps can in bodily tissue, provide partly, for example, the injection of the tumour through in vivo.In the presence of The compounds of this invention, the activation of acceptor takes place, and therefore can study its effect.
Embodiment of the present invention provides in the medical treatment of treating the patient needs S1P acceptor (S1P 1) method of the illness that activates, wherein use compound of the present invention to the patient with the dosage, frequency and the duration that the patient are produced beneficial effect.Compound of the present invention can be used through any suitable manner, and the example as stated.
Some prepares embodiment
Reagent: (i) Zn (CN) 2, Pd (PPh 3) 4, NMP; (ii) RuCl (cymene) [(R, R)-Ts-DPEN], HCO 2The H-TEA compound; (iii) NH 2OH*HCl, Na 2CO 3Or TEA, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.
The (ii) middle use RuCl (cymene) of step [(S, S)-Ts-DPEN] to prepare (S)-enantiomer with route 1 shown same way as.The (ii) middle NaBH that uses of step 4To prepare the racemic material with route 1 shown same way as.
Figure BPA00001577340400421
Reagent: (i) DPPA, DBU, toluene; (ii) PG=blocking group, for example, Boc:Pd/C, H 2, Boc 2O, TEA, MeOH; (iii) NH 2OH*HCl, NaHCO 3, EtOH; (iv) HOBt, EDC, benzoic acid, DMF (v) deprotection, for example, 4M HCl De dioxane solution; (vi) (a) R '-LG or R "-LG, wherein LG representes leaving group, K 2CO 3, CH 3CN; (b) R 1-CO 2H or R 2-CO 2H, HOBt, EDC, DMF or R 1-COCl or R 2-COCl, TEA, DCM; (c) R 1-SO 2Cl or R 3-SO 2Cl, TEA, DCM (d) R 2-CHO, HOAc, NaBH 4Or NaCNBH 3Or Na (OAc) 3BH, MeOH; (e) R 1-OCOCl or R 2-OCOCl, DIEA, DMF; (f) HN (R 5R 5), CDI, TEA, DCM; (g) H 2NSO 2NH 2, Δ ， diox; (h) dimethyl ethylene oxide, Δ, EtOH; (vii) (a) is if R ' or R "=H, then can react (vi) (a-d); (b) if R ' or R " comprise ester, then can carry out (i) hydrolyzing N aOH, EtOH maybe can (ii) reduce NaBH 4, MeOH; (c) if R ' or R " comprise acid, then can carry out coupling HN (R 5R 5), HOBt, EDC, DMF; (d) if R ' or R " comprise the alkene of suitable activation, then can carry out Michael addition HN (R 5R 5), DMF.
With the same way as of being summarized with route 2, from (S)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile begins preparation (R)-enantiomer.
Reagent: (i) sodium borohydride, ethanol, silica gel; (ii) PG=blocking group, for example, tert-butyl group dimethyl chloride monosilane (TBDMS chloride), imidazoles; (iii) (4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-dioxa boron heterocycle pentane)) (4,4,4 ', 4 ', 5,5,5 ', 5 '-octamethyl-2,2 '-bi (1,3,2-dioxaborolane)), PdCl 2(dppf) .CH 2Cl 2, potassium acetate ， diox.
Figure BPA00001577340400431
Reagent: (i) Zn (CN) 2, Pd (PPh 3) 4, NMP; (ii) for the racemic material: sodium borohydride, ethanol, silica gel; For (R)-indanol: (S)-(-)-2-methyl-CBS-oxa-boron pyridine (oxazaborolidine), BH 3-DMS, toluene; For (S)-indanol: (R)-(+)-2-methyl-CBS-oxa-boron pyridine, BH 3-DMS, toluene; (iii) NH 2OH*HCl, Na 2CO 3Or TEA, EtOH.
Figure BPA00001577340400432
Reagent: (i) oxalyl chloride, DCM; (ii) monoethanolamine, Et 3N, DCM; (iii) SOCl 2, DCM, KOH, MeOH be the N-bromo-succinimide (iv), azo isobutyronitrile, DCM; ((for example, TBDMS) 4-(4,4,5,5-tetramethyl-1,3,2-dioxa boron heterocycle pentane-2-yl)-2,3-dihydro-1H-indenes-1-alcohol, the K that v) protect 2CO 3, Pd (PPh 3) 4, DME, H 2O; (vi) deprotection, for example, TBAF, THF; (vii) SOCl 2, DCM; (viii) R '-NH 2Or R "-NH 2, DIPEA, DMA.
Reagent: (i) (R)-2-methylpropane-2-sulfenamide, Ti (OEt) 4, toluene; (ii) NaBH 4, THF; (iii) 4N HCl De dioxane solution, MeOH; (iv) Boc 2O, TEA, DCM; (v) (4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-dioxa boron heterocycle pentane)), PdCl 2(dppf) .CH 2Cl 2, potassium acetate 、 diox; (vi) 5-(5-Xiu Dai oxazole-2-yl)-2-isopropoxy benzonitrile, K 2CO 3, Pd (PPh 3) 4, DME, H 2O; (vii) 4N HCl De dioxane solution; (viii) (a) R '-LG or R "-LG, wherein LG representes leaving group, K 2CO 3, CH 3CN; (b) R 1-CO 2H or R 2-CO 2H, HOBt, EDC, DMF or R 1-COCl or R 2-COCl, TEA, DCM; (c) R 1-SO 2Cl or R 3-SO 2Cl, TEA, DCM (d) R 2-CHO, HOAc, NaBH 4Or NaCNBH 3Or Na (OAc) 3BH, MeOH; (e) R 1-OCOCl or R 2-OCOCl, DIEA, DMF; (f) HN (R 5R 5), CDI, TEA, DCM; (g) H 2NSO 2NH 2, Δ ， diox; (h) dimethyl ethylene oxide, Δ, EtOH; (ix) if (a) R ' or R "=H, then can react (viii) (a-d); (b) if R ' or R " comprise ester, then can carry out (i) hydrolysis, NaOH, EtOH maybe can (ii) reduce NaBH 4, MeOH; (c) if R ' or R " comprise acid, then can carry out coupling HN (R 5R 5), HOBt, EDC, DMF; (d) if R ' or R " comprise suitable activation alkene, then can carry out Michael addition HN (R 5R 5), DMF.
In step (i), can use (S)-2-methylpropane-2-sulfenamide preparation (S)-enantiomer.
Figure BPA00001577340400451
Reagent: (i) HOBt, EDC, 2-(3,4-diethoxy phenyl) acetate, DMF; (ii) SOCl 2, DCM; (iii) R '-NH 2, DIPEA, DMA.
Reagent: (i) Zn (CN) 2, Pd (PPh 3) 4, NMP; (ii) (R)-2-methylpropane-2-sulfenamide, Ti (OEt) 4, toluene; (iii) NaBH 4, THF; (iv) 4M HCl De dioxane solution, MeOH; (v) PG=blocking group, for example, Boc 2O, TEA, DCM; (vi) NH 2OH*HCl, TEA, EtOH; (vii) R '-halide, NaH, DMF.
Figure BPA00001577340400461
Reagent: (i) (a) HOBt, EDC, 2-(3,4-diethoxy phenyl) acetate, DMF (b) deprotection, for example, the dioxane solution of 4N HCl; (ii) (a) R '-LG, wherein, LG representes leaving group, K 2CO 3, CH 3CN; (b) if R ' comprises ester, then (a) uses NaOH, EtOH afterwards; (c) R '-CO 2H, HOBt, EDC, DMF or R '-COCl, TEA, DCM; (d) R '-SO 2Cl, TEA, DCM (e) R '-CHO, HOAc, NaBH 4Or NaCNBH 3Or Na (OAc) 3BH, MeOH.
In step (i), can use (the R)-1-amino-N-hydroxyl-2 of protection, 3-dihydro-1H-indenes-4-carbonamidine preparation (S)-enantiomer.
Figure BPA00001577340400462
Reagent: (i) HOBt, EDC, 4-phenyl-5-(trifluoromethyl) thiophene-2-carboxylic acid, DMF; The (ii) ethereal solution of 2N HCL, DCM.
Route 11:
Figure BPA00001577340400471
Reagent: (i) PG=blocking group, for example, Boc 2O, DMAP, ACN; (ii) NH 2OH*HCl, Na 2CO 3, EtOH; (iii) HOBt, EDC, benzoic acid, DMF; (iv) deprotection, for example, 4N HCl De dioxane solution.
Figure BPA00001577340400472
Reagent: (i) NH 2OH*HCl, Na 2CO 3, EtOH; (ii) HOBt, EDC, benzoic acid, DMF.
Reagent: (i) NH 2OH*HCl, Na 2CO 3, EtOH; (ii) HOBt, EDC, 3-cyanic acid-4-isopropoxy benzoic acid, DMF.
Route 14:
Figure BPA00001577340400481
Reagent: (i) PG=blocking group, for example, tert-butyl group dimethyl chloride monosilane, TEA, DCM; (ii) Zn (CN) 2, Pd (PPh 3) 4, NMP; (iii) NH 2OH*HCl, Na 2CO 3, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.
Embodiment
Universal method
1H NMR (400MHz) and 13C NMR (100MHz) is at deteriochloroform (CDCl 3), deuterated methanol (CD 3OD) or methyl-sulfoxide-D 6(DMSO) obtain in the solution.Use Mestrec 5.3.0 and 6.0.1 to handle the NMR spectrum.In the bracket 13C NMR peak is two kinds of rotational isomers (rotomer) of same carbon.Mass spectrum (LCMS) is to use Agilent 1100/6110 HPLC system to obtain; Said system disposition has Thompson ODS-A, 100A, 5 μ (50X4.6mm) post; The water that use contains 0.1% formic acid is as mobile phase A and use the acetonitrile that contains 0.1% formic acid as Mobile phase B.Gradient is to use the Mobile phase B 2.5min of 20-100%, remains on 100%2.5mins then.Flow velocity is 1mL/min.Only if point out in addition, the LCMS data utilize this method to obtain.For the stronger compound of hydrophobicity, use following gradient, shown in method 1: 40-95%0.5min, remain on 95%8.5min, flow velocity is 1mL/min.Final compound method for using 2 check purity: 5%9min, 5-95% 9min remains on 95% 5min then, and flow velocity is 1mL/min.Through with the flow velocity of 1mL/min and equal strength flowing phase at Chiralpak AD-H, the integration at the peak that separates on the 250x4.6mm post is confirmed enantiomeric excess.Only if point out in addition, the chirality data utilize this method to obtain.Perhaps, carry out chiral separation under the condition below, as shown in the chirality method 1: Chiralpak AY-H, 250x4.6mm post, flow velocity: 1mL/min; With equal strength flowing phase.Chirality method 2:Chiralcel OZ-3,150x4.6mm post, flow velocity: 0.75mL/min; With equal strength flowing phase.The pyridine that in this process, uses, carrene (DCM), oxolane (THF) and toluene all are from remaining on nitrogen (N 2) under Aldrich Sure-Seal bottle.All reactions are all under magnetic agitation, and temperature is the external reaction temperature.Use is equipped with the (SiO of Redisep (Teledyne Isco) silica gel 2) the Combiflash Rf fast purifying system (Teledyne Isco) of post carries out chromatography.The preparation HPLC purifying carries out in Varian ProStar/PrepStar system, use the water comprise 0.05% trifluoroacetic acid as mobile phase A and the acetonitrile that comprises 0.05% trifluoroacetic acid as Mobile phase B.Gradient is the Mobile phase B 12min of 10-80%, remains on 80%2min, is back to 10%2min then, and flow velocity is 22mL/min.Can use other method similarly.Use Varian Prostar level to divide gatherer to collect level and divide, and use Savant SpeedVac Plus vavuum pump to evaporate.But the compound with salify center (salt-able center) is assumed to trifluoroacetic acid (TFA) salt.Use is equipped with the Biotage Initiator microwave reactor of Biotage microwave container to carry out heating using microwave.Used following abbreviation among this paper: ethyl acetate (EA), triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIEA), hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), isopropyl alcohol (IPA), dimethyl formamide (DMF), dimethylacetylamide (DMA).Norit is an active carbon.
Experimentation
5-oxo-5,6,7,8-naphthane-1-nitrile (INT-1)
To the 5-bromo-3 that stirs, (9.95g adds Zn (CN) in NMP 44.2mmol) (50mL) solution to 4-dihydronaphthalene-1 (2H)-ketone 2(10.38g, 88.4mmol).Through in solution, blasting N 230min makes the mixture degassing twice, vacuumizes then.Add Pd (Ph 3) 4(0.5g, 0.44mmol), and at N 2Down mixture is heated to 110 ℃.Behind 5h, mixture is cooled to room temperature, and is poured on the ice (600mL), water (300mL) is accomplished shifted.Behind ice-out, filtering solution, and the solid of collection gained are suspended among the DCM, and filter once more.Collect solid, use water washing, and with purified (EA/hex) to obtain the white solid 5-oxo-5,6,7 of 6.9g (91%), 8-naphthane-1-nitrile INT-1.LCMS-ESI (m/z) C 11H 9The calculated value of NO: 171.2; Measured value: 172.1[M+H] +, t R=2.95min. 1H NMR (400MHz, CDCl 3) δ 8.26 (dd, J=7.9,1.4Hz, 1H), 7.82 (dd, J=7.6,1.4Hz, 1H), 7.44 (t, J=7.8Hz, 1H), 3.20 (t, J=6.1Hz, 2H), 2.72 (dd, J=7.2,6.1Hz, 2H), 2.30-2.17 (m, 2H). 13C?NMR(101MHz，CDCl 3)δ196.22，147.39，137.18，133.39，131.59，127.19，116.93，112.94，38.48，28.05，22.28。
(R)-and 5-hydroxyl-5,6,7,8-naphthane-1-nitrile (INT-2)
To the 5-oxo-5,6,7 that stirs, 8-naphthane-1-nitrile INT-1 (3.0g, 17.5mmol) 5: 1HCO 2: NEt 3(24mL) add in the solution RuCl (cymene) [(R, R)-Ts-DPEN] (0.13g, 0.26mmol).Under 30 ℃, stirred the mixture 15 hours, then at EA and H 2Distribute among the O.The organic layer Na that merges 2SO 4Drying, and chromatography (EA/hex) is with (R)-5-hydroxyl-5,6,7 of the white solid that obtains 2.99g (99%), 8-naphthane-1-nitrile INT-2.LCMS-ESI (m/z) C 11H 11The calculated value of NO: 173.2; Measured value: 174.1[M+H] +, 156.1[M-NH 4] +, t R=2.60min. 1H NMR (400MHz, CDCl 3) δ 7.71 (d, J=7.8Hz, 1H), 7.54 (dt, J=8.7,4.4Hz, 1H), 7.34-7.26 (m; 1H), 4.85-4.71 (m, 2H), 3.48 (s, 1H), 3.13-2.96 (m, 1H), 2.90 (ddd; J=17.7,7.8,5.6Hz, 1H), 2.15-1.95 (m, 2H), 1.97-1.76 (m, 2H).Chirality HPLC: (R)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile is with 5%IPA/ hexane wash-out.99.1％ee，t R＝15.3min。
Use INT-1 and RuCl (cymene) [(S, S)-Ts-DPEN] prepare (S)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile INT-3 in a similar fashion.Chirality HPLC:99.4%ee, (S)-t of enantiomer R=17.99min.
The preparation of general program 1. amidoximes (amide oxime)
In the EtOH solution (0.56M) of (R)-or (S)-cyanide (1 equivalent), add hydroxylamine hydrochloride (3 equivalent) and NaHCO 3Or TEA (3 equivalent), mix 1-2h 85 ℃ of following reacting by heating.Distribute separation organic soluble amidoxime through the removal of solvent and between water and DCM.The water-soluble amide oxime carries out chromatography or directly is used in the cyclisation.Can obtain pure amidoxime through recrystallization in alcoholic solvent.
(R)-and N, 5-dihydroxy-5,6,7,8-naphthane-1-carbonamidine (INT-4)
Figure BPA00001577340400502
Use general program 1 preparation.To (the R)-5-hydroxyl-5,6,7 that stirs, 8-naphthane-1-nitrile INT-2 (79.1mg, EtOH 0.46mmol) (2mL) solution add hydroxylamine hydrochloride (34.9mg, 0.50mmol) and sodium bicarbonate (42.2mg, 0.50mmol).At 70 ℃ of following heating blends 18h.Product is through white solid (the R)-N of chromatography (MeOH/DCM) purifying to obtain 27.3mg (29%), 5-dihydroxy-5,6,7,8-naphthane-1-carbonamidine INT-4.LCMS-ESI (m/z) C 11H 11The calculated value of NO: 173.2; Measured value: 174.1[M+H] +, 156.1[M-NH 4] +, t R=2.60min.In a similar fashion by (S)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile INT-3 prepares (S)-N, 5-dihydroxy-5,6,7,8-naphthane-1-carbonamidine INT-5.
General program 2. cyclisation Wei oxadiazole amine
At room temperature, N 2Nitrogen stirs the DMF solution (0.08M is in acid) of suitable acid (1 equivalent), HOBt (1.3 equivalent) and EDC (1.3 equivalent) down.After being completed into HOBt-acid compound (1-3h), (R)-or (S)-amidoxime (1.1eq) is joined in the mixture.After being completed into the intermediate of coupling (about 0.5-2h), heating blends is accomplished (8-12h) to 75-95 ℃ until cyclisation.With saturated NaHCO 3Diluted reaction mixture, and extract with EA.The dry organic extract that merges concentrates, and can pass through chromatography (EA/ hexane), preparation HPLC or recrystallization purifying.
(R)-5-(3-(5-hydroxyl-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (compound 1).
Figure BPA00001577340400511
Use universal process 2 preparations.To the 3-cyanic acid-4-isopropoxy benzoic acid that stirs (16.7mg, DMF 0.08mmol) (1mL) solution add HOBt (14.3mg, 0.11mmol) and EDCI (20.3mg, 0.11mmol).After stirring 30 minutes, add (R)-N, 5-dihydroxy-5,6,7,8-naphthane-1-carbonamidine INT-4 (27.3mg, DMF 0.09mmol) (1.5mL) solution.After at room temperature stirring 60min again, mixture is heated to 90 ℃ keeps 15h.Mixture dilutes with EA, and uses NaHCO 3Washing.The dry organic layer that merges, concentrate, chromatography (EA/ hexane) is with (R)-5-(3-(5-hydroxyl-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-the yl)-2-isopropoxy benzonitrile of the white solid that obtains 12.72mg (42.4%).LCMS-ESI (m/z) C 22H 21N 3O 3Calculated value: 375.4; Measured value: 376.1[M+H] +, t R=3.73min. 1H NMR (400MHz, CDCl 3) δ 8.42 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9,2.2Hz, 1H); 7.97 (dd, J=7.7,1.3Hz, 1H), 7.66 (d, J=7.2Hz, 1H); 7.38 (t, J=7.7Hz, 1H), 7.12 (d, J=9.0Hz, 1H), 4.91-4.83 (m; 1H), 4.79 (dq, J=12.0,6.0Hz, 1H), 3.20 (dt, J=17.8; 5.4Hz, 1H), 3.01 (dt, J=13.3,6.4Hz, 1H), 2.13-1.81 (m; 4H), 1.79 (d, J=7.2Hz, 1H), 1.47 (d, J=5.6Hz, 6H). 13C?NMR(101MHz，CDCl 3)δ172.70，169.48，162.75，140.10，137.4，134.13，133.88，131.68，129.96，126.18，125.97，116.82，115.26，113.54，103.95，72.73，68.47，31.62，28.50，21.73，18.57。Chirality HPLC: (R)-5-(3-(5-hydroxyl-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile is with 10%IPA/ hexane wash-out: 99.4%ee, t R=40.85min.
In a similar fashion by (S)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile INT-5 prepares (S)-5-(3-(5-hydroxyl-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 2.Chirality HPLC:99.1%ee, (S)-t of enantiomer R=38.19min.
(S)-and 5-azido-5,6,7,8-naphthane-1-nitrile (INT-6)
Figure BPA00001577340400521
Will be at N 2(the R)-5-hydroxyl-5,6,7 that stirs under the atmosphere, (3.00g, toluene 17.32mmol) (16mL) solution is cooled to 0 ℃ to 8-naphthane-1-nitrile INT-2.Add DPPA (9.53g, 34.64mmol), then in 20min, dropwise add DBU (3.16mL, 20.78mmol).The 4h that under 0 ℃, stirs the mixture slowly is warmed up to room temperature then in 2h, concentrate then.The crude mixture of gained is diluted with EA, and uses NaHCO 3Washing.With the organic layer that brine wash merges, use Na 2SO 4Drying, and white solid (the S)-5-azido-5,6,7 of chromatography (EA/ hexane) to obtain 2.49g (72.6%), 8-naphthane-1-nitrile INT-6.LCMS-ESI (m/z) C 11H 10N 4Calculated value: 198.2; Measured value: 156.1[M-N 3] +, t R=3.65min. 1H NMR (400MHz, CDCl 3) δ 7.60 (dd, J=7.6,1.2Hz, 1H), 7.56 (dd, J=7.8,0.6Hz, 1H); 7.33 (t, J=7.7Hz, 1H), 4.59 (t, J=4.4Hz, 1H), 3.08 (dt, J=18.0; 5.1Hz, 1H), and 2.99-2.83 (m, 1H), 2.15-1.96 (m, 3H), 2.00-1.81 (m, 1H). 13C?NMR(101MHz，DMSO)δ141.05，135.58，133.47，132.66，126.58，117.43，113.21，58.74，28.28，27.54，18.27。
In a similar fashion by (S)-5-hydroxyl-5,6,7,8-naphthane-1-nitrile INT-3 preparation (R)-5-azido-5,6,7,8-naphthane-1-nitrile INT-7.
(S)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) t-butyl carbamate (INT-8)
Figure BPA00001577340400531
To (the S)-5-azido-5,6,7 that stirs, (3.1g, MeOH 15.63mmol) (50mL) solution adds 10%Pd/C (500mg), (Boc) to 8-naphthane-1-nitrile INT-6 2O (6.83g, 31.27mmol) and Et 3N (3.16g, 31.27mmol).Use H 2(3x) purging and flushing reactant mixture, and at H 2The following stirring.Behind 3h, use the diatomite filtration mixture, clean with MeOH.Concentrate MeOH filtrating, be dissolved among the EA, and use NaHCO 3And brine wash.Dry organic layer (MgSO 4), concentrate and chromatography (EA/ hexane).Material crystallization white solid (S)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) t-butyl carbamate INT-8 in hexane with gained to obtain 3.45g (81%).LCMS-ESI (m/z) C 16H 20N 2O 2Calculated value: 272.34; Measured value: 156.1[M-NHBoc] +, t R=3.77min. 1H NMR (400MHz, CDCl 3) δ 7.60 (d, J=7.8Hz, 1H), 7.53 (d, J=7.5Hz, 1H), 7.31-7.20 (m, 1H), 4.86 (s; 1H), 4.75 (d, J=8.9Hz, 1H), 3.06-2.85 (m, 2H), 2.07 (dt, J=11.3; 5.1Hz, 1H), 1.91 (s, 2H), 1.86-1.71 (m, 1H), 1.48 (s, 9H). 13C?NMR(101MHz，CDCl 3)δ155.38，140.70，139.12，133.03，131.63，126.41，117.62，112.42，79.62，48.25，29.75，28.28，27.77，19.36。Chirality HPLC: with 2.5%EtOH/ hexane wash-out (S)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) t-butyl carbamate: 92.4%ee, t R=14.22min.
In a similar fashion by (R)-5-azido-5,6,7,8-naphthane-1-nitrile INT-7 preparation (R)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) t-butyl carbamate INT-9.Chirality HPLC:99.6%ee, (R)-t of enantiomer R=11.60min.
(S)-(5-(N-hydroxy formamidine base)-1,2,3,4-naphthane-1-yl) t-butyl carbamate (INT-10)
Figure BPA00001577340400532
Use general program 1 preparation.To (S)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) the t-butyl carbamate INT-8 that stirs (3.10g, add in EtOH 11.38mmol) (25mL) solution hydroxylamine hydrochloride (2.77g, 39.84mmol) and NEt 3(3.17mL, 22.77mmol).Behind heating 15h after 85 ℃, enriched mixture heavily is dissolved among the DCM, and uses NaHCO 3Washing.The dry organic layer that merges, concentrated also chromatography (MeOH/DCM) are to obtain 3.56g rough (S)-(5-(N-hydroxy formamidine base)-1; 2,3,4-naphthane-1-yl) t-butyl carbamate INT-10 (58% product; Press the UV area), it is used to need not to be further purified in next reaction.LCMS-ESI (m/z) C 16H 23N 3O 3Calculated value: 305.37; Measured value: 306.2[M+H] +, t R=2.00min.
In a similar fashion by (R)-(5-cyanic acid-1,2,3,4-naphthane-1-yl) t-butyl carbamate INT-9 preparation (R)-(5-(N-hydroxy formamidine base)-1,2,3,4-naphthane-1-yl) t-butyl carbamate INT-11.
(S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) t-butyl carbamate (INT-12)
Figure BPA00001577340400541
Use general program 2 preparations.To the 3-cyanic acid-4-isopropoxy benzoic acid that stirs (556mg, add in DMF 2.72mmol) (10mL) solution HOBt (476.6mg, 3.53mmol) and EDCI (677.9mg, 3.53mmol).After stirring 30min minute, add (S)-(5-(N-hydroxy formamidine base)-1,2,3,4-naphthane-1-yl) t-butyl carbamate INT-10 (3.56g crude product, about 2.99mmol).After at room temperature stirring 90min again, mixture is heated to 90 ℃ of 15h.Mixture dilutes with EA, and uses NaHCO 3Washing.The dry organic layer that merges, concentrate (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) the t-butyl carbamate INT-12 of chromatography (EA/ hexane) with the white solid that obtains 1.89g (46%).LCMS-ESI (m/z) C 27H 30N 4O 4Calculated value: 474.6; Do not observe M/Z, t R=4.23min. 1H NMR (400MHz, CDCl 3) δ 8.42 (d, J=2.1Hz, 1H), 8.33 (dd, J=8.9,2.2Hz, 1H); 7.92 (dd, J=7.7,1.1Hz, 1H), 7.56 (d, J=7.6Hz; 1H), 7.32 (dd, J=20.3,12.6Hz, 1H), 7.12 (d; J=9.0Hz, 1H), 4.94 (d, J=6.0Hz, 1H), 4.88-4.72 (m; 1H), and 3.23-3.08 (m, 1H), 3.07-2.94 (m, 1H), 2.06 (d; J=12.6Hz, 1H), 1.97-1.78 (m, 3H), 1.53-1.43 (m, 15H). 13C?NMR(101MHz，CDCl 3)δ172.64，169.40，162.69，155.43，138.65，137.55，134.04，133.83，131.68，129.55，126.08，125.97，116.74，115.20，113.53，103.87，79.44，72.69，48.97，29.73，28.40，21.68，19.71，14.14。
In a similar fashion by (R)-(5-(N-hydroxy formamidine base)-1,2,3; 4-naphthane-1-yl) t-butyl carbamate INT-11 preparation (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-base-1; 2,3,4-naphthane-1-yl) t-butyl carbamate INT-13.
(S)-5-(3-(5-amino-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (compound 4)
Figure BPA00001577340400551
To (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1 that stirs; 2; 3,4-naphthane-1-yl) (0.90g 1.9mmol) adds 4N HCl/ diox (2.5mL) to t-butyl carbamate INT-12 in De diox (10mL) solution.60 ℃ down stir 5.5h after, enriched mixture is with the hydrochloride of (the S)-5-of the white solid that obtains 0.8g (100%) (3-(5-amino-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 4.Through the pure sample of preparation HPLC purity analysis, and pass through at NaHCO 3And distribution preparation unhindered amina between the EA.LCMS-ESI (m/z) C 22H 22N 4O 2Calculated value: 374.4; Measured value: 358.1[M-NH 2] +, t R=2.45min. 1H NMR (400MHz, DMSO) δ 8.63 (s, 2H), 8.50 (d, J=2.2Hz; 1H), 8.39 (dd, J=9.0,2.3Hz, 1H); 7.95 (dd, J=7.7,1.0Hz, 1H), 7.85 (d; J=7.5Hz, 1H), 7.56 (d, J=9.2Hz, 1H); 7.49 (t, J=7.7Hz, 1H), 4.98 (hept; J=6.0Hz, 1H), 4.55 (t, J=5.3Hz; 1H), 3.11 (dt, J=17.9,5.5Hz; 1H), 2.94 (dt, J=13.9,6.1Hz; 1H), and 2.18-1.88 (m, 3H), 1.88-1.71 (m; 1H), 1.38 (d, J=6.0Hz, 6H). 13C?NMR(101MHz，DMSO)δ172.91，168.60，162.52，137.73，134.60，134.09，133.80，132.08，130.30，126.29，126.06，115.92，115.24，114.93，102.49，72.54，66.34，48.02，27.57，26.54，21.47，17.68。Chirality HPLC: use the 8%EtOH/ hexane, with 0.3%DEA wash-out (S)-5-(3-(5-amino-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (chirality method 1): 94.2%ee, t R=42.7min.
With similar method by (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) ((5-amino-5 for 3-for t-butyl carbamate INT-13 preparation (R)-5-; 6,7,8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 3.Chirality HPLC (chirality method 1): 99.9%ee, (R)-t of enantiomer R=39.72min.
The preparation of general program 3. naphthane ureas
In DCM (0.16M) solution of the CDI (1.2 equivalent) that stirs, add (R)-or (S)-tetrahydro naphthylamine (1 equivalent) and Et 3The DCM solution (0.01M) of N (3 equivalent).After stirring 15h, at room temperature this solution is joined and comprise suitable amine (3 equivalent) and Et 3In second solution (0.4M) of N (3 equivalent) in DCM.The mixture that at room temperature stirs gained is consumed until all initiation materials.Evaporating solvent, and behind preparation HPLC the separation of pure product.
Use general program 3 preparation compound 5-20.
(S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-3-hydroxy azetidine-1-formamide (compound 8)
Figure BPA00001577340400561
Use general program 3 preparations: LCMS-ESI (m/z) C 26H 27N 5O 4Calculated value: 473.5; Measured value: 474.2[M+H] +, t R=3.21min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9,2.2Hz; 1H), 7.91 (dd, J=7.7,1.2Hz, 1H), 7.53 (t; J=6.1Hz, 1H), 7.32 (dd, J=20.1,12.4Hz, 1H); 7.12 (d, J=9.0Hz, 1H), 5.13 (d, J=8.0Hz; 1H), 4.79 (dt, J=12.2,6.1Hz, 1H); 4.68 (tt, J=6.7,4.4Hz, 1H), 4.35 (d; J=8.7Hz, 1H), 4.25-4.14 (m, 2H), 3.85 (dd; J=8.8,4.1Hz, 2H), 3.14 (t, J=12.1Hz; 1H), and 3.10-2.92 (m, 1H), 2.16-1.96 (m, 1H); 1.99-1.64 (m, 4H), 1.48 (d, J=6.1Hz, 6H).Chirality HPLC: the water with 15%/MeOH wash-out (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-3-hydroxy azetidine-1-formamide (chirality method 2): 91.4%ee, t R=15.52min.
Prepare (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-3-hydroxy azetidine-1-formamide 7 in a similar fashion.Chirality HPLC:99.94%ee, t R=17.17min (chirality method 2).
(S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) pyrrolidines-1-formamide (compound 12).
Figure BPA00001577340400562
Use general program 3 preparations: LCMS-ESI (m/z) C 27H 29N 5O 3Calculated value: 471.55; Measured value: 472.2[M+H] +, t R=3.78min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.1Hz, 1H), 8.32 (dd, J=8.9; 2.2Hz, 1H), 7.90 (dd, J=7.6,1.1Hz; 1H), 7.59 (d, J=7.6Hz, 1H), 7.33 (t; J=7.7Hz, 1H), 7.12 (d, J=9.0Hz, 1H); 5.25-5.12 (m, 1H), 4.79 (hept, J=6.0Hz; 1H), 4.45 (t, J=21.8Hz, 1H); 3.36 (t, J=6.4Hz, 4H), 3.23-3.09 (m; 1H), 3.02 (dt, J=18.0,6.0Hz; 1H), and 2.16-1.99 (m, 1H), 2.01-1.79 (m; 7H), 1.47 (d, J=6.1Hz, 6H).
(S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) morpholine-4-formamide (compound 15)
Figure BPA00001577340400571
Use general program 3 preparations: LCMS-ESI (m/z) C 27H 29N 5O 4Calculated value: 487.5; Measured value: 488.2[M+H] +, t R=3.58min. 1H NMR (400MHz, CDCl 3) δ 8.40 (d, J=2.2Hz, 1H), 8.32 (dd, J=8.9; 2.2Hz, 1H), 7.91 (dd, J=7.7,1.1Hz; 1H), 7.55 (t, J=10.0Hz, 1H), 7.33 (t; J=7.7Hz, 1H), 7.12 (d, J=9.0Hz, 1H); 5.19 (dd, J=12.9,5.3Hz, 1H), 4.86-4.75 (m; 1H), 4.72 (d, J=8.1Hz, 1H), 3.76-3.63 (m; 4H), 3.36 (dd, J=11.6,7.1Hz, 4H); 3.16 (dt, J=16.7,5.4Hz, 1H), 3.02 (dt; J=12.6,5.9Hz, 1H), 2.14-1.98 (m, 2H); 1.94-1.81 (m, 2H), 1.47 (d, J=6.1Hz, 6H).
(R)-N-((R)-5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) 3-(dimethylamino) pyrrolidines-1-formamide (compound 20)
Figure BPA00001577340400572
Use general program 3 preparations: ((9.5mg dropwise adds (R)-5-(3-(5-amino-5,6 in DCM 0.06mmol) (1mL) solution to the CDI that stirs; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-and 2-isopropoxy benzonitrile hydrochloride 3 (20mg, 0.05mmol) and Et 3N (20.3 μ L, DCM 0.15mmol) (1mL) solution.After at room temperature stirring 15h, (18.6mg is in another solution 0.15mmol) at room temperature this solution dropwise to be joined (the R)-3-dimethylamino pyrrolidines that comprises among the DCM (1mL).Reaction stirred 6.5h at room temperature.Evaporating solvent, and through (R)-N-((R)-5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2 of preparation HPLC separation of pure product to obtain 17.5mg (70%); 4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) 3-(dimethylamino) pyrrolidines-1-formamide 20.LCMS-ESI (m/z) C 29H 34N 6O 3Calculated value: 514.6; Measured value: 515.3[M+H] +, t R=2.56min. 1H NMR (400MHz, CDCl 3) δ 8.39 (d, J=2.2Hz, 1H), 8.31 (dt, J=8.7,4.3Hz; 1H), 7.91 (d, J=7.6Hz, 1H), 7.52 (d, J=7.6Hz; 1H), 7.34 (t, J=7.7Hz, 1H), 7.12 (d, J=9.2Hz; 1H), 5.13 (d, J=6.9Hz, 1H), 4.86-4.73 (m, 1H); 4.64 (d, J=8.2Hz, 1H), 3.91 (dd, J=10.4,7.3Hz; 1H), and 3.80-3.56 (m, 3H), 3.41 (dd, J=17.5,8.3Hz; 1H), 3.15 (d, J=18.0Hz, 1H), 3.10-2.93 (m; 1H), 2.85 (s, 6H), 2.46 (m, 2H); 2.05 (dd, J=9.2,4.8Hz, 1H), 1.88 (m; 3H), 1.45 (dd, J=13.9,6.1Hz, 6H).
General program 4: prepare the naphthane acid amides through acid chloride
In the DCM solution of (R) that stir-or (S)-tetrahydro naphthylamine hydrochloride (1 equivalent), add acid chloride (2 equivalent) and NEt 3(2 equivalent).Reaction stirred 1h at room temperature.Evaporating solvent, and through the preparation HPLC purified mixture.
Use general program 4 preparation compound 21-25.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) acetamide (compound 21)
Figure BPA00001577340400581
Use general program 4 preparations: ((5-amino-5,6,7 for 3-to (the R)-5-that stirs; 8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 3 (20mg; 0.05mmol) DCM (0.5mL) solution in add chloroacetic chloride (7 μ L, 0.10mmol) and NEt 3(14 μ L, 0.10mmol).After stirring 1h, evaporating solvent, and through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3, the 4-naphthane-1-yl) acetamide (compound 21) of preparation HPLC purifying residue to obtain 11.3mg (56%).LCMS-ESI (m/z) C 24H 24N 4O 3Calculated value: 416.5; Measured value: 417.2[M+H] +, t R=3.56min. 1H NMR (400MHz, CDCl 3) δ 8.40 (d, J=2.2Hz, 1H), 8.32 (dd, J=8.9,2.2Hz, 1H), 7.92 (dd; J=7.7,1.2Hz, 1H), 7.48 (d, J=7.6Hz, 1H), 7.33 (t; J=7.7Hz, 1H), 7.12 (d, J=9.0Hz, 1H), 5.83 (d, J=8.6Hz; 1H), 5.36-5.21 (m, 1H), 4.79 (hept, J=6.0Hz, 1H), 3.16 (dt; J=17.9,6.0Hz, 1H), 3.03 (dt, J=18.2,6.3Hz, 1H); 2.10-1.99 (m, 4H), 1.97-1.79 (m, 3H), 1.47 (d, J=6.1Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) acetamide 22.
General program 5: the preparation of naphthane sulfonamides amine
(add sulphamide (5 equivalent) and DIEA (3 equivalent) in the 1 equivalent) De dioxane solution to (R) that stir-or (S)-tetrahydro naphthylamine hydrochloride.At 110 ℃ of following reaction stirred 18h.Evaporating solvent, and through the preparation HPLC purified mixture.
Use general program 5 preparation compounds 26 and 27.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) sulfonamides amine (compound 26)
Figure BPA00001577340400591
Use general program 5 preparations: ((5-amino-5 for 3-to (the R)-5-that stirs; 6; 7; 8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 3 (50mg; 0.12mmol add sulphamide (58mg in) De diox (3mL) solution; 0.61mmol) and DIEA (47.2 μ L 0.37mmol), and are heated to 110 ℃ of 14h with mixture.Evaporating solvent, and through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) the sulfonamides amine 26 of preparation HPLC purifying residue to obtain 22.8mg (42%).LCMS-ESI (m/z) C 22H 23N 5O 4The calculated value of S: 453.5; Measured value: 454.1[M+H] +, t R=3.47min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9; 2.2Hz, 1H), 7.97 (dd, J=7.7,1.2Hz; 1H), 7.72 (d, J=7.7Hz, 1H), 7.38 (t; J=7.8Hz, 1H), 7.12 (d, J=9.0Hz, 1H); 4.78 (ddd, J=13.4,11.7,5.7Hz, 2H); 4.59 (d, J=19.8Hz, 2H), 4.55 (d, J=8.2Hz; 1H), 3.19 (dt, J=18.0,5.6Hz, 1H); 3.02 (dt, J=18.2,7.2Hz, 1H), 2.23-2.03 (m; 2H), 1.92 (dt, J=12.4,6.3Hz; 2H), 1.48 (d, J=6.1Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) sulfonamides amine 27.
General program 6: prepare the naphthane sulfonamide through sulfonic acid chloride
At room temperature the DCM solution (0.05M) to (R)-or (S)-tetrahydro naphthylamine hydrochloride (1 equivalent) adds TEA (2 equivalent) and suitable sulfonic acid chloride (1-2 equivalent).Stirred reaction mixture 18h at room temperature.Evaporating solvent, and behind the preparation HPLC purifying separated product.
Use general program 6 preparation compound 28-33.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) Methanesulfomide (compound 28)
Figure BPA00001577340400601
Use general program 6 preparations: ((5-amino-5 for 3-to (the R)-5-that stirs under 0 ℃; 6; 7; 8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 3 (20mg, DCM 0.05mmol) (1mL) solution adds TEA (20 μ L; 0.15mmol) and mesyl chloride (4.5 μ L, 0.06mmol).In 2h, make mixture be warming up to room temperature, evaporating solvent, and through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 of preparation HPLC purifying crude mixture to obtain 12.8mg (58%); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) Methanesulfomide (compound 28).LCMS-ESI (m/z) C 23H 24N 4O 4The calculated value of S: 452.5; Measured value: 453.1[M+H] +, t R=3.68min. 1H NMR (400MHz, CDCl 3) δ 8.40 (t, J=3.5Hz, 1H), 8.32 (dd, J=8.9,2.2Hz, 1H); 7.96 (dd, J=7.7,1.1Hz, 1H), 7.67 (d, J=7.7Hz, 1H); 7.38 (t, J=7.7Hz, 1H), 7.16-7.07 (m, 1H), 4.88-4.70 (m, 1H); 4.54 (d, J=8.4Hz, 1H), 3.19 (dt, J=18.0,5.9Hz, 1H); 3.10 (d, J=5.0Hz, 3H), 3.09-2.95 (m, 1H), 2.14 (qt, J=14.5; 7.3Hz, 1H), 2.06-1.83 (m, 3H), 1.47 (t, J=5.5Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) Methanesulfomide 29.
(S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-methoxyl group ethyl sulfonamide (compound 31)
Figure BPA00001577340400602
Use the cyclopropane sulfonic acid chloride through general program 6 preparations.LCMS-ESI (m/z) C 25H 26N 4O 4The calculated value of S: 478.6; Measured value: 479.1[M+H] +, t R=3.84min.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-methoxyl group ethyl sulfonamide (compound 32)
Use 2-methoxyl group ethyl sulfonic chloride through general program 6 preparations.LCMS-ESI (m/z) C 25H 28N 4O 5The calculated value of S: 496.58; Measured value: 519.1[M+Na] +, t R=3.83min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9,2.2Hz, 1H); 7.99-7.92 (m, 1H), 7.74 (d, J=7.6Hz, 1H), 7.37 (t, J=7.7Hz; 1H), 7.12 (d, J=9.0Hz, 1H), 4.85-4.71 (m, 2H), 4.68-4.60 (m; 1H), and 3.93-3.76 (m, 2H), 3.47-3.31 (m, 5H), 3.17 (dt; J=18.0,6.0Hz, 1H), 3.02 (dt, J=18.1,6.7Hz; 1H), 2.20-1.82 (m, 4H), 1.48 (d, J=6.1Hz, 6H).Chirality HPLC: (R)-water/MeOH wash-out (chirality method 2) of N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-methoxyl group ethyl sulfonamide 32 usefulness 10%: 99.98%ee, t R=21.07min.
In a similar fashion by 4 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-methoxyl group ethyl sulfonamides 33.Chirality HPLC:99.04%ee, t R=18.57min (chirality method 2).
(R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) sulfamoyl) methyl acetate (INT-14).
Figure BPA00001577340400612
Use general program 6 preparations: ((5-amino-5 for 3-to (the R)-5-that stirs; 6; 7; 8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-(0.15g adds TEA (76 μ L to 2-isopropoxy benzonitrile hydrochloride 3 in the solution of DCM 0.37mmol) (5mL); 0.55mmol) and 2-(chlorosulfonyl) methyl acetate (76mg, 0.44mmol).Add extra TEA and 2-(chlorosulfonyl) methyl acetate and be reflected at completion in 24 hours with driving.Make rough reactant mixture at DCM and saturated NaHCO 3Between distribute.Organic layer Na 2SO 4Drying concentrates, and through (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) sulfamoyl) the methyl acetate INT-14 of column chromatography (EA/ hexane) purifying to obtain 0.11g (57%).LCMS-ESI (m/z) C 25H 26N 4O 6The calculated value of S: 510.6; Measured value: 511.1[M+H] +, t R=3.73min. 1H NMR (400MHz, CDCl 3) δ 8.42 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9,2.2Hz, 1H); 8.01-7.93 (m, 1H), 7.74 (d, J=7.8Hz, 1H), 7.39 (t, J=7.8Hz; 1H), 7.12 (d, J=9.0Hz, 1H), 5.00 (d, J=8.4Hz, 1H); 4.81 (dq, J=18.3,5.9Hz, 2H), 4.25-4.00 (m, 2H), 3.83 (s; 3H), 3.20 (dt, J=18.1,5.9Hz, 1H), 3.12-2.97 (m, 1H); 2.22-2.01 (m, 2H), 2.02-1.83 (m, 2H), 1.48 (d, J=6.1Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) sulfamoyl) methyl acetate INT-15.
General program 7: the preparation of naphthane sulphonyl amino acid
At room temperature, adding 6N NaOH (2 equivalent) in the MeOH solution (0.2M) of (R) that stir-or (S)-naphthane sulfonamide ester (1 equivalent).Reaction stirred 6h at room temperature.Rough reactant dilute with water, with 1N HCl acidifying, and with DCM and EA extraction.Organic layer Na 2SO 4Drying concentrates, and behind the preparation HPLC purifying, separates.
Use general program 7 preparation compounds 34 and 35.
(R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) sulfamoyl) acetate (compound 34)
Figure BPA00001577340400621
Use general program 7 preparations: to (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2; 3; 4-naphthane-1-yl) sulfamoyl) (0.082g adds 6N NaOH (0.08mL) to methyl acetate INT-14 in MeOH 0.16mmol) (1.5mL) solution.Reaction stirred 6h at room temperature.Rough reactant dilute with water, with 1N HCl acidifying, and with DCM and EA extraction.Organic layer Na 2SO 4Drying concentrates, and behind the preparation HPLC purifying, separates (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3, the 4-naphthane-1-yl) sulfamoyl) acetate 34 to obtain 0.057g (72%).Prepare analytically pure sample through the preparation HPLC purifying.LCMS-ESI (m/z) C 24H 26N 4O 6The calculated value of S: 496.5; Measured value: 520.1[M+Na] +, t R=3.47min.
In a similar fashion by (S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) methyl acetate INT-15 preparation (S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 sulfamoyl); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) sulfamoyl) acetate 35.
General program 8: the preparation of naphthane sulfonamide alcohol
At room temperature, adding sodium borohydride (2.5 equivalent) in the THF solution (0.06M) of (R) that stir-or (S)-naphthane sulfonamide ester (1 equivalent).Reactant mixture is heated to 75 ℃, and dropwise adds methyl alcohol (1 equivalent).Behind 1h, make the reactant cooling, concentrate, and through the preparation HPLC purifying.
Use general program 8 preparation compounds 36 and 37.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-hydroxyl ethyl sulfonamide (compound 37)
Figure BPA00001577340400631
Use general program 8 preparations: at room temperature; To (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) sulfamoyl) methyl acetate INT-14 (0.025g; 0.05mmol) the solution of THF (25mL) in add sodium borohydride (0.05g, 0.12mmol).With reaction mass heated to 75 ℃, and add methyl alcohol (0.02mL, 0.05mmol).Behind 1h, the cooling reaction thing also concentrates and through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-the yl)-2-hydroxyl ethyl sulfonamide 37 of preparation HPLC purifying to obtain 16.0mg (66%).LCMS-ESI (m/z) C 24H 26N 4O 5The calculated value of S: 482.6; Measured value: 505.1[M+Na] +, t R=3.46min. 1H NMR (400MHz, CDCl 3) δ 8.39 (dd, J=5.4,2.4Hz, 1H), 8.35-8.25 (m, 1H), 7.95 (dt; J=7.7,3.9Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.43-7.32 (m; 1H), 7.12 (t, J=7.5Hz, 1H), 4.80 (m, 3H), 4.12 (t; J=5.2Hz, 2H), 3.46-3.28 (m, 2H), 3.17 (dt, J=18.0,5.9Hz; 1H), 3.02 (dt, J=18.1,6.8Hz, 1H), 2.68 (s, 1H); 2.12 (m, 1H), 2.07-1.82 (m, 3H), 1.47 (d, J=6.1Hz, 6H). 13C?NMR(101MHz，CDCl 3)δ172.82，169.22，162.81，137.73，136.90，134.12，133.89，132.15，130.28，126.46，126.33，116.65，115.22，113.57，103.93，72.78，57.32，56.17，52.54，30.60，28.06，21.72，19.04。Chirality HPLC: (R)-water/methanol-eluted fractions (chirality method 2) of N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-hydroxyl ethyl sulfonamide 37 usefulness 15%: 99.82%ee, t R=22.23min.
In an identical manner by (S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) methyl acetate INT-15 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 sulfamoyl); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl)-2-hydroxyl ethyl sulfonamide 36.Chirality HPLC:91.7%ee, t R=19.83min (chirality method 2).
The preparation of 9: four naphthalene sulfonylamide acid amides of general program
Adding EDC and N-hydroxybenzotriazole in the DMF solution (0.25M) of (R) that stir-or (S)-naphthane sulphonyl amino acid (1 equivalent).Behind 5min, add amine, and stirred reaction mixture 18h at room temperature.Use NaHCO 3Dilute rough reactant, and extract with EA.The organic layer Na that merges 2SO 4Drying, and through the preparation HPLC purifying.
Use general program 9 preparation compound 38-43.
(R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) sulfamoyl)-N,N-dimethylacetamide (compound 40)
Figure BPA00001577340400641
Use general program 9 preparations: to (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2; 3,4-naphthane-1-yl) sulfamoyl) (15mg adds N-hydroxybenzotriazole (6.1mg to acetate 34 in DMF 0.05mmol) (0.5mL) solution; 0.05mmol) and EDC (8.7mg, 0.05mmol).Behind 5min, add dimethylamine (the THF solution of 40wt%, 50 μ L, 0.09mmol), stirred reaction mixture 18h at room temperature.With saturated NaHCO 3Dilute rough reactant, and extract with EA.With the organic layer Na that merges 2SO 4Drying, and through (R)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) the sulfamoyl)-N,N-dimethylacetamide 40 of preparation HPLC purifying to obtain 4.41mg (28%).LCMS-ESI (m/z) C 26H 29N 5O 5The calculated value of S: 523.6; Measured value: 546.2[M+Na] +, t R=3.58min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.1Hz, 1H), 8.33 (dd, J=8.9,2.2Hz, 1H); 7.96 (dd, J=7.7,1.2Hz, 1H), 7.82 (d, J=7.5Hz, 1H); 7.38 (t, J=7.8Hz, 1H), 7.12 (d, J=9.0Hz, 1H), 5.36 (t; J=17.3Hz, 1H), 4.88-4.73 (m, 2H), 4.27 (d, J=14.6Hz, 1H); 4.07 (d, J=14.6Hz, 1H), 3.24-3.09 (m, 4H), 3.09-2.97 (m, 4H); 2.23-2.08 (m, 2H), 2.10-1.84 (m, 2H), 1.47 (d, J=6.1Hz, 6H). 13C?NMR(101MHz，CDCl 3)δ172.75，169.37，163.15，162.77，137.79，136.92，134.13，133.90，132.50，130.18，126.36，126.17，116.79，115.25，113.55，103.96，72.74，55.46，53.05，38.22，35.98，29.84，28.10，21.73，19.10。
In a similar fashion by (S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3; 4-naphthane-1-yl) acetate 35 preparation ((S)-2-(N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1 sulfamoyl); 2; 3,4-naphthane-1-yl) sulfamoyl)-N,N-dimethylacetamide 41.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) ethene sulfonamide INT-16
Figure BPA00001577340400651
((5-amino-5 for 3-to (the R)-5-that stirs under 0 ℃; 6; 7; 8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-(100mg adds TEA (170 μ L to 2-isopropoxy benzonitrile hydrochloride 3 in DCM 0.24mmol) (5mL) solution; 1.2mmol) and the 2-chloro-ethane-sulfonyl chloride (76 μ L, 0.73mmol).Reactant mixture is warming up to room temperature, and stirred 30 minutes.Remove and to desolvate, and through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2 of chromatography (EA/ hexane) purified product with the white solid that obtains 83.0mg (75%); 4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) ethene sulfonamide INT-16.LCMS-ESI (m/z) C 24H 24N 4O 4The calculated value of S: 464.5; Measured value: 465.1[M+H] +, t R=3.83min. 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=2.2Hz, 1H), 8.32 (dd, J=8.9,2.2Hz; 1H), 7.96 (dd, J=7.7,1.2Hz, 1H), 7.62 (t; J=11.0Hz, 1H), 7.38 (t, J=7.7Hz, 1H), 7.12 (d; J=9.0Hz, 1H), 6.66 (dt, J=26.0,13.0Hz; 1H), 6.38 (d, J=16.5Hz, 1H), 6.03 (dd; J=10.1,5.2Hz, 1H), 4.86-4.73 (m, 1H); 4.68-4.57 (m, 1H), 4.50 (d, J=8.3Hz, 1H); 3.18 (dt, J=18.1,5.8Hz, 1H), 3.02 (dt; J=18.1,6.8Hz, 1H), 2.15-1.96 (m, 2H); 1.97-1.79 (m, 2H), 1.48 (d, J=6.1Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) ethene sulfonamide INT-17.
General program 10: prepare the naphthane sulfonamide through Michael addition
In the DCM solution (0.1M) of (R)-or (S)-naphthane vinyl sulfonamide (1 equivalent), add TEA (5 equivalent) and suitable amine (5 equivalent).Stirred reaction mixture 18h at room temperature.Through the preparation HPLC purified product.
Use general program 10 preparation compound 44-47.
(R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl)-2-(dimethylamino) ethyl sulfonamide (compound 44)
Figure BPA00001577340400661
Use general program 10 preparations.To ((R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1; 2; 3,4-naphthane-1-yl) ethene sulfonamide INT-16 (40mg, the THF solution (0.22mL of adding 2N methylamine in DMF 0.09mmol) (1.0mL) solution; 0.43mmol), and stirred reaction mixture 18h at room temperature.Through (R)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 of preparation HPLC purification of crude product with the white solid that obtains 24.6mg (54%); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl)-tfa salt 44 of 2-(dimethylamino) ethyl sulfonamide.LCMS-ESI (m/z) C 26H 31N 5O 4The calculated value of S: 509.6; Measured value: 510.2[M+H] +, t R=2.61min. 1H NMR (400MHz, CDCl 3) 8.41-8.32 (m, 1H), 8.33-8.26 (m, 1H), 7.92 (t; J=6.9Hz, 1H), 7.61 (t, J=7.2Hz, 1H); 7.35 (dd, J=14.5,7.1Hz, 1H), 7.11 (d; J=9.1Hz, 1H), 4.86-4.64 (m, 2H), 3.61 (ddt; J=27.2,13.7,7.8Hz, 4H); 3.23-3.06 (m, 1H), 3.10-2.91 (m, 1H); 2.93 (d, J=30.3Hz, 6H), 2.09 (ddd; J=28.4,16.5,12.3Hz, 1H); 1.95 (ddd, J=15.1,8.3,3.5Hz; 3H), 1.46 (t, J=6.0Hz, 6H).
In a similar manner by ((S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) ethene sulfonamide INT-17 preparation (S)-N-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl)-2-(dimethylamino) ethyl sulfonamide 45.
(R)-2-isopropoxy-5-(3-(5-((2-(methyl sulphonyl) ethyl) amino)-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (compound 48)
Figure BPA00001577340400671
((5-amino-5,6,7 for 3-to (R)-5-; 8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 3 (20mg; 0.05mmol) DMA (0.5mL) solution in add TEA (136 μ L, 0.97mmol) with the methyl ethylene sulfone (52mg, 0.5mmol).With reaction mass heated to 80 ℃ 24h.Through preparation HPLC purification of crude reactant mixture to obtain (R)-2-isopropoxy-5-(3-(5-((2-(mesyl) ethyl) amino)-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl) benzonitrile 48.LCMS-ESI (m/z) C 25H 28N 4O 4The calculated value of S: 480.6; Measured value: 481.2[M+H] +, t R=2.58min. 1H NMR (400MHz, CDCl 3) 68.37 (t, J=9.1Hz, 1H), 8.31 (dd, J=8.9; 2.2Hz, 1H), 8.08 (d, J=7.1Hz, 1H); 7.60 (d, J=7.6Hz, 1H), 7.42 (t, J=7.7Hz; 1H), 7.12 (d, J=9.1Hz, 1H), 4.85-4.73 (m; 1H), 4.53 (t, J=5.0Hz, 1H), 3.63 (dd; J=15.3,4.0Hz, 2H), 3.61-3.50 (m, 2H); 3.33-3.17 (m, 1H), 3.18-3.04 (m, 1H), 3.04 (d; J=8.6Hz, 3H), 2.16 (ddd, J=29.6,18.8; 12.2Hz, 2H), 2.00 (dd, J=36.4,18.4Hz; 2H), 1.47 (d, J=6.1Hz, 6H).
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6,7,8-naphthane-1-yl)-1; 2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile hydrochloride 4 preparation (S)-2-isopropoxy-5-(3-(5-((2-(mesyl) ethyl) amino)-5,6,7; 8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl) benzonitrile, compound 49.
(R)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) methyl acetate (INT-18)
To (the R)-5-that stirs (3-(5-amino-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 3 (119mg, CH 0.32mmol) 3Add in CN (5.0mL) solution methyl bromoacetate (53.5 μ L, 0.35mmol) and K 2CO 3(138mg, 1.27mmol).After stirring 18h, mixture dilutes with salt solution, and uses NaHCO 3Washing.Organic layer Na 2SO 4Drying, and concentrate.With the rough solid of gained through (R)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) the methyl acetate INT-18 of chromatography (MeOH/DCM) purifying to obtain 113.1mg (79%).LCMS-ESI (m/z) C 25H 26N 4O 4Calculated value: 446.5; Measured value: 447.2[M+H] +, t R=2.52min.
((5-amino-5 for 3-by (S)-5-in a similar fashion; 6; 7,8-naphthane-1-yl)-1,2; 4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 4 preparation (S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) amino) methyl acetate INT-19.
(S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) methyl acetate (INT-20)
Figure BPA00001577340400681
To (the S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2; 3,4-naphthane-1-yl) amino) (128.0mg adds Boc acid anhydrides (125.1mg to methyl acetate INT-19 in DCM 0.29mmol) (6.0mL) solution; 0.57mmol) and TEA (120 μ L, 0.86mmol).After stirring 18h, enriched mixture.With the rough solid of gained through chromatography (EA/ hexane) purifying (S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 to obtain 119mg (76%); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) amino) methyl acetate INT-20.LCMS-ESI (m/z) C 30H 34N 4O 6Calculated value: 546.61; Do not observe M/Z, t R=4.32min.
In a similar fashion by (R)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) methyl acetate INT-18 preparation (R)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 amino); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) amino) methyl acetate INT-21.
(S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) (2-hydroxyethyl) t-butyl carbamate (INT-22)
Figure BPA00001577340400682
Under 75 ℃ to (S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1 that stirs; 2,3,4-naphthane-1-yl) amino) methyl acetate INT-20 (35mg; 0.06mmol) THF (6.0mL) solution in add sodium borohydride (6mg, 0.16mmol).After stirring 0.5h, (7.7 μ L, 0.19mmol), and mixture heats 1.5h again to add MeOH.Enriched mixture, and (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2 of solid through chromatography (EA/ hexane) purifying gained to obtain 16mg (48%); 4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) (2-hydroxyethyl) t-butyl carbamate INT-22.LCMS-ESI (m/z) C 29H 34N 4O 5Calculated value: 518.6; Measured value: 419.2[M-Boc+H] +, t R=4.10min.
In a similar fashion by (R)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) methyl acetate INT-21 preparation (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 amino); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) (2-hydroxyethyl) t-butyl carbamate INT-23.
General program 11: the Boc deprotection of tetrahydro naphthylamine
In (R) of the Boc protection of stirring-or (S)-tetrahydro naphthylamine De dioxane solution, add 4N HCl/ diox (4-10 equivalent).At 50 ℃ of following reacting by heating mixture 18h.Concentrated reaction mixture, and the solid through preparation HPLC purifying gained.
Use general program 11 preparation compound 50-53.
(R)-5-(3-(5-((2-hydroxyethyl) amino)-5,6,7,8-naphthane-1-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (compound 50)
Figure BPA00001577340400691
Use general program 11 preparations.To (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2; 3; 4-naphthane-1-yl) (2-hydroxyethyl) t-butyl carbamate INT-23 (15mg, 0.03mmol) add in De diox (1mL) solution 4N HCl/ diox (116 μ L, 0.116mmol).Behind heating 18h under 50 ℃, enriched mixture, and through (R)-5-(3-(5-((2-hydroxyethyl) amino)-5 of preparation HPLC purifying gained solid to obtain 9.53mg (79%); 6,7,8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 50.LCMS-ESI (m/z) C 24H 26N 4O 3Calculated value: 418.5; Measured value: 419.2[M+H] +, t R=2.52min. 1H NMR (400MHz, CDCl 3) δ 8.39 (d, J=2.2Hz, 1H), 8.32 (dd, J=8.9,2.2Hz, 1H); 8.04 (d, J=7.7Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.39 (t; J=7.7Hz, 1H), 7.12 (d, J=9.1Hz, 1H), 4.88-4.70 (m, 1H); 4.54 (s, 1H), 3.78 (d, J=12.1Hz, 2H), 3.62 (s, 2H); 3.24 (dt, J=18.0,5.6Hz, 1H), 3.18-2.89 (m, 3H), 2.16 (d; J=5.2Hz, 2H), 2.10-1.75 (m, 2H), 1.47 (d, J=6.1Hz, 6H).
In a similar fashion by (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) (2-hydroxyethyl) t-butyl carbamate INT-22 preparation (S)-5-(3-(5-((2-hydroxyethyl) amino)-5; 6,7,8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile 51.
(S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) acetate (INT-24)
(93.2mg adds 10 1N NaOH in MeOH 0.17mmol) (2ml) solution to (S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) the methyl acetate INT-20 that stirs.Under 50 ℃, stirred the mixture 2 hours, and used H then 2O dilutes, and neutralizes with 1N HCl.The aqueous solution is with DCM and EA extraction.The organic layer Na that merges 2SO 4Drying, and concentrate (S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) acetate INT-24 with the white solid that obtains 61mg (67%).LCMS-ESI (m/z) C 29H 32N 4O 6Calculated value: 532.6; Measured value: 358.1[M-2-((tert-butoxycarbonyl) amino) acetate] +, t R=3.97min.
In a similar fashion by (S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) methyl acetate INT-21 preparation (R)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 amino); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) amino) acetate INT-25.
(S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) acetate (compound 53)
Use general program 11 preparations.At room temperature stir (S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) amino) acetate INT-24 (30mg; 0.06mmol) at 4N HCl/ diox (200 μ l, 50mmol) the solution 18h in.Enriched mixture, and through the tfa salt of preparation HPLC purifying residue with (S)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) amino) acetate 53 of obtaining 21mg (67%).LCMS-ESI (m/z) C 24H 24N 4O 4Calculated value: 432.5; Measured value: 358.1[M-2-amion acetic acid] +, t R=2.65min.
In a similar fashion by (R)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) acetate INT-25 preparation (R)-2-((5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 amino); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) amino) acetate 52.
The preparation of 12: four naphthylamino acid amides of general program
Add N-hydroxybenzotriazole (2 equivalent) and EDC (2 equivalent) to (R) of Boc protection-or (S)-naphthane amino acid DMF.Behind 10min, add suitable amine (10 equivalent), and stirred reaction mixture 18h at room temperature.Use NaHCO 3Dilute crude reaction mixture, and extract with EA.The organic layer Na that merges 2SO 4Drying, and through the preparation HPLC purifying.
Use general program 12 preparation compounds 54 and 55.
(S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1,2,3,4-naphthane-1-yl) (2-oxo-2-(pyrrolidines-1-yl) ethyl) t-butyl carbamate (INT-26)
Use general program 12 preparations.To (S)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 that stirs; 2; 4-oxadiazole-3-yl)-1; 2; 3,4-naphthane-1-yl) amino) (30mg adds N-hydroxybenzotriazole (15.21mg to acetate INT-24 in DMF 0.06mmol) (0.5mL) solution; 0.11mmol) and EDC (21.63mg, 0.11mmol).Behind 10min, add pyrrolidines (46 μ L, 0.56mmol), and stirred reaction mixture 18h at room temperature.With saturated NaHCO 3Dilute said rough reactant, and extract with EA.With the organic layer Na that merges 2SO 4Drying, and through (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2 of preparation HPLC purifying to obtain 26.9mg (82%); 4-oxadiazole-3-yl)-1; 2,3,4-naphthane-1-yl) (2-oxo-2-(pyrrolidines-1-yl) ethyl) t-butyl carbamate.LCMS-ESI (m/z) C 33H 39N 5O 5Calculated value: 585.7; Measured value: 358.1[M-(2-oxo-2-(pyrrolidines-1-yl) ethyl) carbamic acid tertiary butyl ester] +, t R=4.18min.
In a similar fashion by (R)-2-((tert-butoxycarbonyl) (5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) acetate INT-25 preparation (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1 amino); 2,4-oxadiazole-3-yl)-1,2; 3,4-naphthane-1-yl) (2-oxo-2-(pyrrolidines-1-yl) ethyl) t-butyl carbamate INT-27.
(R)-2-isopropoxy-5-(3-(5-((2-oxo-2-(pyrrolidines-1-yl) ethyl) amino)-5,6,7,8-tetrahydrochysene how-1-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (compound 54)
Use general program 11 preparations.At room temperature stir (R)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1; 2; 3; 4-naphthane-1-yl) (2-oxo-2-(pyrrolidines 1-yl) ethyl) t-butyl carbamate INT-27 (18mg, 0.03mmol) solution 18h in 4N HCl/ diox (1mL).Concentrated reaction mixture, and through (the R)-2-isopropoxy-5-(3-(5-((2-oxo-2-(pyrrolidines-1-yl) ethyl) amino)-5,6 of preparation HPLC purifying to obtain 12mg (68%); 7; 8-naphthane-1-yl) tfa salt of benzonitrile 54-1,2,4-oxadiazole-5-yl).LCMS-ESI (m/z) C 28H 31N 5O 3Calculated value: 485.6; Measured value: 486.2[M+H] +, t R=2.60min. 1H NMR (400MHz, CDCl 3) δ 8.40 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.9,2.2Hz; 1H), 8.07 (d, J=7.6Hz, 1H), 7.77 (d, J=7.6Hz; 1H), 7.44 (t, J=7.7Hz, 1H), 7.13 (d, J=9.1Hz; 1H), and 4.87-4.68 (m, 2H), 3.98-3.80 (m, 2H), 3.53-3.03 (m; 7H), 2.17 (ddd, J=17.7,10.4,5.5Hz, 3H); 2.04-1.79 (m, 5H), 1.48 (d, J=6.1Hz, 6H).
In a similar fashion by (S)-(5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2; 4-oxadiazole-3-yl)-1,2,3; 4-naphthane-1-yl) (2-oxo-2-(pyrrolidines-1-yl) ethyl) t-butyl carbamate INT-26 preparation (S)-2-isopropoxy-5-(3-(5-((2-oxo-2-(pyrrolidines-1-yl) ethyl) amino)-5; 6,7,8-naphthane-1-yl)-1; 2,4-oxadiazole-5-yl) benzonitrile 55.
4-bromo-2,3-dihydro-1H-indenes-1-alcohol (INT-28)
Figure BPA00001577340400722
Under 0 ℃ to the 4-bromine indone that stirs (3g, add in anhydrous EtOH (30mL) solution 14.2mmol) sodium borohydride (0.36g, 9.5mmol) and silica gel (2g).At 0 ℃ of following reaction stirred 20min, and make it at room temperature stir 2h.Reactant mixture is with saturated NaHCO 3Cancellation, and concentrate to remove EtOH.Water layer extracts with EA, organic facies MgSO 4Dry.After concentrating, through chromatography (EA/ hexane) purification of crude product to obtain the 4-bromo-2 of white solid, 3-dihydro-1H-indenes-1-alcohol INT-28 (2.56g, 85%).LCMS-ESI (m/z) C 9H 9The calculated value of BrO: 213.1; Measured value: 195.0[M-H 2O] +, t R=3.07min. 1H NMR (400MHz, CDCl 3) δ 7.35 (d, J=7.9,1H), 7.27 (d, J=7.4,1H), 7.05 (t, J=7.7,1H); 5.23 (t, J=6.2,1H), 3.00 (ddd, J=16.6,8.8,4.6,1H), 2.84-2.66 (m; 1H), 2.45 (dddd, J=13.2,8.4,7.0,4.6,1H), 1.96-1.70 (m, 2H).
(4-bromo-2,3-dihydro-1H-indenes-1-base oxygen base) (tert-butyl group) dimethyl silane (INT-29)
Figure BPA00001577340400731
To 4-bromo-2,3-dihydro-1H-indenes-1-alcohol INT-28 (2.56g, add in DMF 12.0mm) (5mL) solution TBDMSCl (2.17g, 14.4mmol) and imidazoles (2g, 30.0mmol), and at room temperature stirred reaction mixture spends the night.The dilute with water reactant mixture, and extract with EA.Water and brine wash organic layer, and use MgSO 4Dry.Through chromatography (EA/ hexane) purification of crude product to obtain (4-bromo-2,3-dihydro-1H-indenes-1-base oxygen base) (tert-butyl group) dimethyl silane INT-29 (3.3g, 84%) of limpid oily.LCMS-ESI (m/z) C 15H 23The calculated value of BrOSi: 327.3; Measured value: 195.0[M-OTBS] +, t R=3.07min. 1H NMR (400MHz, CDCl 3) δ 7.20 (d, J=7.8Hz, 1H), 7.06 (d, J=7.4Hz, 1H); 6.92 (t, J=7.7Hz, 1H), 5.13 (t, J=7.0Hz, 1H); 2.85 (ddd, J=16.4,9.1,2.9Hz, 1H); 2.57 (dt, J=16.5,8.3Hz, 1H), 2.36-2.17 (m; 1H), 1.76 (dtd, J=12.8,8.8,7.1Hz; 1H), and 0.83-0.72 (m, 9H), 0.05--0.06 (m, 6H).
Tert-butyl group dimethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxa boron heterocycle pentane-2-yl)-2,3-dihydro-1H-indenes-1-base oxygen base) monosilane (INT-30)
Figure BPA00001577340400732
Through with N 2Be passed into (4-bromo-2,3-dihydro-1H-indenes-1-base oxygen base) (tert-butyl group) dimethyl silane INT-29 (50mg, 0.15mmol), (4; 4,4 ', 4 '; 5,5,5 '; 5 '-prestox-2,2 '-two (1,3; 2-dioxa boron heterocycle pentane)) (42mg; 0.16mmol) and potassium acetate (45mg, 0.45mmol) anhydrous 1, the 5min degassing in 4-diox (2mL) solution.Add PdCl then 2(dppf) .CH 2Cl 2, and 85 ℃ of following reacting by heating mixture overnight.Under vacuum, remove and desolvate, residue dilutes with EA (10mL), and through diatomite filtration to remove solid.Water and brine wash filtrating, and use MgSO 4Dry.Through chromatography (EA/ hexane) purification of crude product to obtain white semi-solid tert-butyl group dimethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxo bora pentamethylene-2-yl)-2,3-dihydro-1H-indenes-1-base-oxygen base) monosilane INT-30 (26mg, 45%).LCMS-ESI (m/z) C 21H 35BO 3The calculated value of Si: 374.4; Measured value: 245.0[M-OTBS] +, t R=3.07min. 1H NMR (400MHz, CDCl 3) δ 7.57-7.43 (m, 1H), 7.21 (dd, J=11.0,4.2Hz, 1H), 7.08-7.01 (m; 1H), 5.06 (t, J=7.0Hz, 1H), 3.11 (ddd, J=16.8; 8.9,3.0Hz, 1H), 2.72 (dt, J=16.8,8.3Hz; 1H), 2.22 (dddd, J=12.6,7.9,7.1,3.1Hz; 1H), 1.71 (dtd, J=12.6,8.8,7.0Hz, 1H); 1.21-1.10 (m, 12H), 0.81-0.71 (m, 9H), 0.03--0.07 (m, 6H).
5-(4,5-dihydro-oxazole-2-yl)-2-isopropoxy benzonitrile (INT-31)
Figure BPA00001577340400741
(1.0g, (3.7g 29.2mmol), then adds two DMF to add oxalyl chloride in DCM 4.8mmol) (20mL) suspension to the 3-cyanic acid-4-isopropoxy benzoic acid that stirs.At 50 ℃ of following stirred reaction mixture 2h.Enriched mixture, and residue is dissolved among the DCM (10mL) again.Add monoethanolamine (0.6g, 9.7mmol) and TEA (1.45g, 14.4mmol), and at room temperature stirred reaction mixture spends the night.Filter the solid of gained, use water washing, and dry 3-cyanic acid-N-(2-hydroxyethyl)-different third oxy benzamide of 4-to obtain 1.0g (83%), it is used for next step and need not purifying.LCMS-ESI (m/z) C 13H 16N 2O 3Calculated value: 248.3; Measured value: 249.0[M+H] +, t R=2.41min. 1H NMR (400MHz, CDCl 3) δ 8.02-7.79 (m, 2H), 6.97-6.87 (m, 1H), 6.71 (s, 1H), 4.65 (dt, J=12.1,6.1Hz, 1H), 3.82-3.70 (m, 2H), 3.56 (dd, J=10.2,5.5Hz, 2H), 1.96 (d, J=10.0Hz, 1H), 1.40-1.29 (m, 6H).
3-cyanic acid-N-(2-hydroxyethyl)-4-isopropoxy benzamide is dissolved among the DCM (30mL), and under 0 ℃, add thionyl chloride (1.43g, 12mmol).Stirred reaction mixture 1h at room temperature is then in 0 ℃ of following water (200L) and 6N NaOH solution (1mL) cancellation.30min stirs the mixture.Water layer extracts with DCM, with the organic layer of brine wash merging, and uses MgSO 4Dry 5-(4,5-dihydro-oxazole-2-yl)-2-isopropoxy benzonitrile INT-31 to obtain 570mg (61%, two step).LCMS-ESI (m/z) C 13H 14N 2O 2Calculated value: 230.3; Measured value: 231.0[M+H] +, t R=2.50min. 1H NMR (400MHz, CDCl 3) δ 8.17-7.86 (m, 2H), 6.91 (d, J=8.9Hz, 1H), 4.65 (dt, J=12.2,6.1Hz, 1H), 4.37 (dd, J=14.3,4.9Hz, 2H), 3.98 (t, J=9.5Hz, 2H), 1.36 (t, J=5.5Hz, 6H).
5-(5-Xiu oxazole-2-yl)-2-isopropoxy benzonitrile (INT-32)
Figure BPA00001577340400751
At N 2Down; 5-(4,5-dihydro-oxazole-2-the yl)-2-isopropoxy benzonitrile INT-31 of 80 ℃ of following heated and stirred (420mg, 1.82mmol), N-bromine succinamide (990mg; 5.56mmol) and azo isobutyronitrile (14.9mg, carbon tetrachloride 0.09mmol) (20mL) solution 18h.Make reactant mixture be cooled to room temperature, and pass through solids removed by filtration.With sodium thiosulfate (20mL) and salt solution (20mL) wash filtrate, and use MgSO 4Dry.Through 5-(5-Xiu oxazole-2-the yl)-2-isopropoxy benzonitrile INT-32 of chromatography (EA/ hexane) purified product with the yellow solid that obtains 300mg (55%).LCMS-ESI (m/z) C 13H 11BrN 2O 2Calculated value: 307.1; Measured value: 309.0[M+2] +, t R=3.79min. 1H NMR (400MHz, CDCl 3) δ 8.19-7.93 (m, 2H), 7.08-6.85 (m, 2H), 4.81-4.47 (m, 1H), 1.38 (dd, J=6.6,3.0Hz, 6H).
General program 13: the coupling of heteroaryl bromide and indanol borate
In the 20mL microwave tube, add successively heteroaryl bromide (1 equivalent), (R)-, (S)-or racemic indanol dioxa boron heterocycle pentane (1 equivalent), DME/H 2O (3: 1,0.05M) and potash (3 equivalent).Through with N 2Gas is blown into that 10min outgases to mixture in the solution of stirring.Add Pd (PPh 3) 4(0.07eq), and again make mixture degasification 2min.This pipe is added a cover, and under 100 ℃, carries out the microwave radiation and accomplish (40-60min) until reaction.If desired, add extra bromide.This pipe is cooled to room temperature,, and uses the hydration brine wash, use MgSO with EA (10x volume) dilution 4Drying, and concentrate.Through silica gel column chromatography (EA/ hexane) purification of crude product.
5-(5-(1-(t-butyldimethylsilyloxy base)-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile (INT-33)
Figure BPA00001577340400761
Use general program 13 preparations.In the microwave tube of 20mL, add 5-(5-Xiu oxazole-2-yl)-2-isopropoxy benzonitrile INT-32 (200mg; 0.65mmol), (4-(4 for tert-butyl group dimethyl; 4; 5,5-tetramethyl-1,3; 2-dioxa boron heterocycle pentane-2-yl)-2; 3-dihydro-1H-indenes-1-base oxygen base) monosilane INT-30 (243mg, 0.65mmol), (269mg is 1.95mmol) with dimethyl ethylene glycol/H of 3: 1 for potash 2The mixture of O (10mL).Through with N 2Be blown into that 10min gives the reactant mixture degasification in the solution of stirring.Add Pd (PPh 3) 4, and give solution degasification 2min again.This pipe carries out microwave radiation 40min under 100 ℃.This pipe is cooled to 0 ℃; And through filtering the solid of collecting gained; With frozen water washing, and dry 5-(5-(1-(t-butyldimethylsilyloxy base)-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile INT-33 with the light yellow solid that obtains 290mg (94%).LCMS-ESI (m/z) C 28H 34N 2O 3The calculated value of Si: 474.7; Measured value: 475.2[M+H] +, t R=5.90min (method 1). 1H?NMR(400MHz，CDCl 3)δ8.16-7.96(m，2H)，7.57-7.42(m，1H)，7.24-7.12(m，3H)，6.90(t，J＝10.4Hz，1H)，5.14(t，J＝7.0Hz，1H)，4.57(dt，J＝12.3，6.1Hz，1H)，3.04(ddd，J＝16.1，9.1，3.1Hz，1H)，2.78(dt，J＝16.1，8.1Hz，1H)，2.43-2.24(m，1H)，1.84(ddd，J＝15.8，12.8，8.9Hz，1H)，1.27(t，J＝5.8Hz，6H)，0.86-0.61(m，9H)，0.06--0.14(m，6H)。
5-(5-(1-hydroxyl-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile (compound 56)
Figure BPA00001577340400762
Under 0 ℃ to 5-(5-(1-(t-butyldimethylsilyloxy base)-2; 3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile INT-33 (350mg; 0.737mmol) anhydrous THF (2mL) solution in add THF (3.6mL, 3.6mmol) solution of the tert-butyl group ammonium fluoride of 1M.Reactant mixture was at room temperature stirred 16 hours, use salt solution (5mL) cancellation then.Under vacuum, remove THF, residue water (5mL) dilution, and use the EA aqueous layer extracted.The extract that merges extracts with salt solution, and uses MgSO 4Drying is through the 5-(5-(1-hydroxyl-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile 56 of chromatography purification with the light yellow solid that obtains 220mg (63%).LCMS-ESI (m/z) C 22H 20N 2O 3Calculated value: 360.4; Measured value: 343.0[M-OH] +, t R=2.30min. 1H NMR (400MHz, CDCl 3) δ 8.30 (d, J=2.2Hz, 1H), 8.26 (dd, J=8.9; 2.2Hz, 1H), 7.75 (d, J=7.6Hz, 1H); 7.48 (d, J=7.3Hz, 1H), 7.42 (t, J=7.6Hz; 1H), 7.10 (d, J=8.9Hz, 1H), 5.35 (d; J=4.8Hz, 1H), 4.78 (dt, J=12.2,6.1Hz; 1H), 3.30 (ddd, J=16.4,8.7,4.8Hz; 1H), and 3.13-2.94 (m, 1H), 2.64 (dddd, J=13.3; 8.4,7.1,4.8Hz, 1H), 2.17-2.08 (m; 1H), 1.86 (s, 1H), 1.60 (s, 1H); 1.46 (dd, J=13.9,6.0Hz, 6H).
General program 14: through chlorine displacement preparation indane amine
In DCM (1mL) solution of the indanol (1 equivalent) that stirs, adding thionyl chloride (2 equivalent) under 0 ℃.Stirred reaction mixture 3h at room temperature.Evaporating solvent, and rough chloride is dissolved in the dimethylacetylamide (1mL) again.Add diisopropylethylamine (3 equivalent) and suitable amine (3 equivalent), and spend the night at 70 ℃ of following stirred reaction mixtures.Water (200 μ L) cancellation reactant mixture, and through the preparation HPLC purifying.
Use general program 14 preparation compound 57,58 and 61-64.
5-(5-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile (compound 57)
Figure BPA00001577340400771
Use general program 14 preparations.Under 0 ℃ to the 5-that stirs (5-(1-hydroxyl-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile 56 (and 50mg, add in DCM 0.1mmol) (3mL) solution thionyl chloride (25mg, 0.21mmol).Stirred reaction mixture 3h at room temperature.Evaporating solvent, and rough chloride is dissolved in the dimethylacetylamide (3mL) again.Add isopropyl ethamine (40.8mg, 0.316mmol) and monoethanolamine (19.3mg, 0.31mmol), and 70 ℃ of following reacting by heating mixture overnight.Use NaHCO 3The cancellation reactant mixture, and extract with EA.With the extract that brine wash merges, use MgSO then 4Dry.Product is through the 5-(5-(1-(2-hydroxyethyl amino)-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile 57 of chromatography (10%MeOH/DCM) purifying to obtain 25mg (60%).LCMS-ESI (m/z) C 24H 25N 3O 3Calculated value: 403.5; Measured value: 404.1[M+H] +, t R=2.41min. 1H NMR (400MHz, DMSO) δ 8.18 (t, J=2.3Hz, 1H), 8.08 (dd, J=9.0,2.3Hz; 1H), 7.70 (d, J=7.7Hz, 1H), 7.44 (d, J=17.4Hz, 1H); 7.42-7.32 (m, 1H), 7.30-7.11 (m, 2H), 4.70 (dt, J=12.2,6.1Hz; 2H), 4.39 (s, 1H), 3.40 (t, J=5.0Hz, 2H), 3.18-2.95 (m; 2H), and 2.93-2.75 (m, 1H), 2.73-2.54 (m, 2H), 2.38-2.16 (m; 1H), 1.98-1.78 (m, 1H), 1.15 (d, J=6.0Hz, 6H). 13C?NMR(101MHz，CDCl 3)δ161.35，159.17，151.04，146.60，139.78，132.16，127.43，125.59，125.07，123.99，120.49，116.10，113.90，103.77，72.60，62.95，61.51，48.70，33.27，31.29，29.91，22.02。
5-(5-(1-((R)-1-hydroxy propane-2-base is amino)-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile (compound 58)
Figure BPA00001577340400781
Use general program 14 preparations.LCMS-ESI (m/z) C 25H 27N 3O 3Calculated value: 417.5; Measured value: 418.4[M+H] +, t R=2.49min.
(R)-N-((R)-4-bromo-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide (INT-34)
Figure BPA00001577340400782
To the 4-bromo-2 that stirs, 3-dihydro-1H-1-Indanone (5.0g, 23.6mmol) with (R)-2-methylpropane-2-sulfenamide (3.15g, add in toluene 26.0mmol) (40mL) solution purity titanium tetraethoxide (8.1g, 35.5mmol), and at N 2Down at 60 ℃ of following reacting by heating mixture 18h.In this mixture, add THF (40mL), and the solution of gained is cooled to-78 ℃.Disposable adding sodium borohydride (3.5g, 94.7mmol).At-78 ℃ of following stirred reaction mixture 15min, be warming up to room temperature then, and under this temperature, stir 2h.Before with salt solution and sodium potassium tartrate tetrahydrate cancellation, reactant mixture is cooled to 0 ℃.Add EA, and at room temperature stir the mixture and spend the night, during this period Ti salt deposition.The decant organic layer, and use saturated NH successively 4Cl, water and brine wash.Organic layer MgSO 4Drying is through MgSO 4Pad filters, and concentrates to produce solid-state (R)-N-((R)-4-bromo-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-34 (3.14g, 42%), and it is used for next step and need not purifying.LCMS-ESI (m/z), C 13H 18The calculated value of BrNOS: 317.3; Measured value: 318.0[M+H] +, t R=3.59min. 1H NMR (400MHz, CDCl 3) δ 7.46 (d, J=7.5,1H), 7.34 (d, J=7.9,1H), 7.05 (t, J=7.7; 1H), 4.96-4.77 (m, 1H), 3.39 (d, J=6.8,1H), 3.06-2.86 (m, 1H); 2.82-2.60 (m, 1H), 2.50-2.29 (m, 1H), 2.05-1.81 (m, 1H), 1.16 (s, 9H).
Use (S)-2-methylpropane-2-sulfenamide preparation (S)-N-((S)-4-bromo-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-35 in a similar fashion.
(R)-and 4-bromo-2,3-dihydro-1H-indenes-1-amine (INT-36)
Figure BPA00001577340400791
To rough (R)-N-((R)-4-bromo-2; 3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-34 (3.14g; 9.9mol) MeOH (10mL) solution in add 4N HCl De diox (7.5mL, 30mmol) solution, and at room temperature stir the yellow suspension 2h of gained.With MeOH (5mL) dilution crude reaction mixture, be cooled to 0 ℃, and remove by filter the Ti accessory substance.Concentrated filtrate, and, be cooled to 0 ℃ then with solid backflow 30min in acetonitrile (60mL) of gained.The white solid of collecting gained to be producing (R)-4-bromo-2, the hydrochloride of 3-dihydro-1H-indenes-1-amine INT-36 (1.55g, 63%), and it is used for next step and need not purifying.LCMS-ESI (m/z) C 9H 10The calculated value of BrN: 212.1; Measured value: 197.0[M-NH] +, t R=0.75min. 1H NMR (400MHz, DMSO) δ 8.60 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.57 (d; J=7.9Hz, 1H), 7.39-7.07 (m, 1H), 4.81 (dd, J=7.9,5.6Hz; 1H), and 3.25-2.64 (m, 3H), 2.59-2.32 (m, 1H), 2.21-1.69 (m, 1H).
Can be in a similar fashion by (S)-N-((S)-4-bromo-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-35 preparation (S)-4-bromo-2,3-dihydro-1H-indenes-1-amine INT-37.
(R)-and 4-bromo-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-38)
Figure BPA00001577340400792
To rough (R)-4-bromo-2, (1.55g adds TEA (1.38g in DCM 6.2mmol) (10mL) solution to 3-dihydro-1H-indenes-1-amine hydrochlorate INT-36 under 0 ℃; 13.7mmol); (1.49g, 6.8mmol), and at room temperature stirred reaction mixture spends the night then to add the Boc acid anhydrides.The reactant mixture brine wash, organic layer MgSO 4Dry also filtration.Through chromatography (EA/ hexane) purified product to obtain solid-state (the R)-4-bromo-2 of canescence, 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-38 (1.63g, 84%).LCMS-ESI (m/z) C 14H 18BrNO 2Calculated value: 312.20; Measured value: 197.0[M-NHBoc] +, t R=3.97min. 1H NMR (400MHz, CDCl 3) δ 7.31 (d, J=7.9Hz, 1H), 7.23-7.13 (m, 1H); 7.02 (t, J=7.7Hz, 1H), 5.30-5.07 (m, 1H); 4.69 (d, J=7.5Hz, 1H), 2.93 (ddd, J=16.5; 9.0,3.4Hz, 1H), 2.75 (dt, J=16.5; 8.2Hz, 1H), and 2.60-2.43 (m, 1H), 1.73 (dq; J=13.1,8.4Hz, 1H), 1.41 (s, 9H).
Can be in a similar fashion by (S)-4-bromo-2,3-dihydro-1H-indenes-1-amine INT-37 preparation (S)-4-bromo-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-39.
(R)-and 4-(4,4,5,5-tetramethyl-1,3,2-dioxa boron heterocycle pentane-2-yl)-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-40)
Figure BPA00001577340400801
Through in solution, feeding N 25min makes (R)-4-bromo-2, and (300mg is 0.96mmol) with (4 for 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-38; 4,4 ', 4 '; 5,5,5 '; 5 '-prestox-2,2 '-two (1,3; 2-dioxa boron heterocycle pentane)) (268mg; 1.0mmol), potassium acetate (283mg, 2.88mmol) anhydrous 1, the degasification of 4-diox (5mL) solution.Add PdCl 2(dppf) .DCM (157mg, 0.19mmol), and 85 ℃ of following reacting by heating mixture overnight.Under vacuum, remove and desolvate, residue is dissolved among the EA (10mL), and through diatomite filtration to remove solid.Water and brine wash filtrating are used MgSO 4Drying, and through chromatography (EA/ hexane) purifying to obtain semi-solid (the R)-4-of white (4,4,5,5-tetramethyl-1,3,2-dioxa boron heterocycle pentane-2-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-40 (265mg, 77%).LCMS-ESI (m/z) C 20H 30BNO 4Calculated value: 359.3; Measured value: 383.0[M+Na] +, t R=4.26min. 1H NMR (400MHz, CDCl 3) δ 7.71 (d, J=7.3Hz, 1H), 7.42 (t, J=7.9Hz, 1H), 7.24 (dd; J=9.7,5.2Hz, 1H), 5.19 (dd, J=15.9,7.9Hz; 1H), 4.72 (d, J=8.5Hz, 1H), 3.28 (ddd, J=17.0; 8.8,3.6Hz, 1H), 2.99 (dt, J=16.8,8.4Hz; 1H), and 2.69-2.44 (m, 1H), 1.77 (ddd, J=16.4,12.8; 8.6Hz, 1H), 1.51 (s, 9H), 1.39-1.31 (m, 12H).
Can be in a similar fashion by (S)-4-bromo-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-39 prepares (S)-4-(4,4; 5,5-tetramethyl-1,3; 2-dioxa boron heterocycle pentane-2-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-41.
(R)-4-(2-(3-cyanic acid-4-isopropyl phenyl) oxazole-5-yl)-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-42)
Figure BPA00001577340400802
Use general program 13 preparations.In the microwave tube of 20mL, add (R)-4-(4; 4; 5; 5-tetramethyl-1,3,2-dioxa boron heterocycle pentane-2-yl)-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-32 (58.4mg; 0.16mmol), 5-(5-Xiu oxazole-2-yl)-2-isopropoxy benzonitrile INT-40 (50mg, 0.16mmol), (68mg is 0.5mmol) with dimethyl ethylene glycol/H of 3: 1 for potash 2The mixture of O (2mL).Through blasting N 2Gas makes the reactant mixture degassing through the solution 10min that stirs.Add Pd (PPh 3) 4((3.9mg 0.004mmol), and makes solution degasification 2min again.Under 100 ℃, make this pipe carry out microwave radiation 30min.Remove and desolvate, and residue is dissolved among the EA (10mL), use brine wash, use MgSO then 4Dry.Through (R)-4-(2-(3-cyanic acid-4-isopropyl phenyl) oxazole-5-yl)-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-42 of chromatography (EA/ hexane) purified product with the pale solid that obtains 50mg (67%).LCMS-ESI (m/z) C 27H 29N 3O 4Calculated value: 459.5; Measured value: 460.2[M+H] +, t R=4.1min. 1H NMR (400MHz, CDCl 3) δ 8.32-8.03 (m, 2H), 7.60 (dd, J=8.6,4.1Hz, 1H); 7.32-7.22 (m, 3H), 7.00 (d, J=8.9Hz, 1H), 5.19 (dd; J=15.5,7.5Hz, 1H), 4.82-4.56 (m, 2H), 3.12 (ddd; J=16.3,9.0,3.5Hz, 1H), 2.95 (dt, J=16.3; 8.1Hz, 1H), and 2.70-2.51 (m, 1H), 1.83 (dq, J=13.1; 8.2Hz, 1H), 1.43 (s, 9H), 1.41-1.35 (m, 6H).
Can be in a similar fashion by (S)-4-(4; 4; 5; 5-tetramethyl-1; 3; 2-dioxa boron heterocycle pentane-2-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-41 preparation (S)-4-(2-(3-cyanic acid-4-isopropyl phenyl) oxazole-5-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-43.
(R)-5-(5-(1-amino-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy-benzonitrile hydrochloride (compound 59)
Figure BPA00001577340400811
To (R)-4-(2-(3-cyanic acid-4-isopropyl phenyl) oxazole-5-yl)-2 that stirs; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-42 (48mg; 0.1mmol) 1, add 1 of 4N HCl in 4-diox (1mL) solution, 4-diox (1mL) solution.At 55-65 ℃ of following stirred reaction mixture 48h.Reactant mixture Et with cooling 2O (10mL) dilution.Collect the solid of gained, and under high vacuum dry (R)-5-(5-(1-amino-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile hydrochloride 59 with the white solid that obtains 32mg (78%).LCMS-ESI (m/z) C 22H 21N 3O 2Calculated value: 359.4; Measured value: 343.1[M-NH 2] +, t R=2.40min. 1H NMR (400MHz, DMSO) δ 8.55 (br s, 2H), 8.43 (dd, J=6.5; 2.4Hz, 1H), 8.32 (ddd, J=6.7,6.1; 2.9Hz, 1H), 8.00 (t, J=13.5Hz, 1H); 7.72 (s, 1H), 7.66 (d, J=7.5Hz, 1H); 7.49 (dd, J=8.5,6.3Hz, 2H), 4.93 (dt; J=12.1,6.0Hz, 1H), 4.81 (s; 1H), and 3.43-3.25 (m, 1H), 3.23-3.04 (m; 1H), and 2.67-2.55 (m, 1H), 2.11 (ddd; J=14.2,9.0,5.9Hz, 1H); 1.36 (dd, J=13.8,7.0Hz, 6H).
Can be in a similar fashion by (S)-4-(2-(3-cyanic acid-4-isopropyl phenyl) oxazole-5-yl)-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-43 preparation (S)-5-(5-(1-amino-2,3-dihydro-1H-indenes-4-base) oxazole-2-yl)-2-isopropoxy benzonitrile hydrochloride INT-44.
1-oxo-2,3-dihydro-1H-indenes-4-nitrile (INT-45)
Figure BPA00001577340400821
To the 4-bromo-2 that stirs, 3-dihydro-1H-1-Indanone (100.0g, add in the 1-methyl of 150mL 0.48mol)-2-pyrrolidines (NMP) solution zinc cyanide (111.8g, 0.95mol) and tetrakis triphenylphosphine palladium [Pd (PPh 3) 4] (2.75g, 0.024mol).Use N 2Make the solution degasification, and at 95 ℃ of following reacting by heating mixture 7h.After cooling, reactant mixture is poured on the frozen water (3.5L).Compound and inorganic zinc salt deposition.Collect solid, and between DCM and water, distribute.Filter organic layer removing Zn salt, and concentrated filtrate and in the mixture of 4: 1 EtOH and MeOH (400mL) crystallization to obtain light yellow solid-state 1-oxo-2,3-dihydro-1H-indenes-4-nitrile INT-45.LCMS-ESI (m/z) C 10H 7The calculated value of NO: 157.2; Measured value: 158.1[M+H] +, t R=2.67min. 1H NMR (400MHz, CDCl 3) δ 8.00-7.90 (m, 1H), 7.86 (dd, J=7.5,1.1,1H), 7.50 (t, J=7.6,1H), 3.40-3.19 (m, 2H), 2.90-2.61 (m, 2H). 13C?NMR(101MHz，CDCl 3)δ204.70，157.90，138.38，137.88，128.44，128.28，116.31，111.70，36.01，25.49。
(±)-1-hydroxyl-2,3-dihydro-1H-indenes-4-nitrile (INT-46)
Figure BPA00001577340400822
To the 1-oxo-2 that stirs, (1.2g 7.64mmol) and in the EtOH suspension of silica gel (catalysis) adds NaBH to 3-dihydro-1H-indenes-4-nitrile INT-45 under 0 ℃ 4(237.2mg, 7.64mmol).Make reactant be warming up to room temperature, and stir 2h.Under reduced pressure remove and desolvate, through chromatography (EA/ hexane) purified product to obtain the 1-hydroxyl-2 of 1.02g (82%) white solid state, 3-dihydro-1H-indenes-4-nitrile INT-46.LCMS-ESI (m/z) C 10H 9The calculated value of NO: 159.2; Measured value: 160.1[M+H] +, t R=2.39min.
N, 1-dihydroxy-2,3-dihydro-1H-indenes-4-carbonamidine (INT-47)
Figure BPA00001577340400831
Use general program 1 preparation.To hydroxylamine hydrochloride (0.87g, 12.5mmol) and sodium carbonate ((1.80g, 11.3mmol), and heated solution is to refluxing for 3-dihydro-1H-indenes-4-nitrile INT-46 for 1.32g, disposable adding 1-hydroxyl-2 in EtOH 12.5mmol) (20mL) solution.Behind 16h, make the reactant cooling, and filter to remove solid.Remove EtOH, and through the N of chromatography (MeOH/DCM) purifying compounds with the white foam shape that obtains 1.74g (90%), 1-dihydroxy-2,3-dihydro-1H-indenes-4-carbonamidine INT-47.LCMS-ESI (m/z) C 10H 12N 2O 2Calculated value: 192.1; Measured value: 193.1[M+H] +, t R=0.56min. 1H NMR (400MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m; 2H), 5.22 (t, J=6.5,1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H); 2.49 (dddd, J=11.4,8.0,7.0,4.4,1H), 2.02-1.88 (m, 1H).
4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol (compound 60)
Figure BPA00001577340400832
Use general program 2 preparations.At room temperature use HOBt (197.8mg, 1.46mmol) and EDC (207.3mg 1.08mmol) handles 2-(3,4-diethoxy phenyl) acetate (180.0mg, DMF 0.80mmol) (3mL) solution.Reaction stirred 2h is until being completed into HOBt-acid compound.Add N-1-dihydroxy-2,3-dihydro-1H-indenes-4-carbonamidine INT-47 (185.1mg, 0.96mmol), and the 2h that at room temperature stirs the mixture, be heated to 80 ℃ of 16h then.Use NaHCO 3Diluted reaction mixture, and extract with EA.Organic facies MgSO 4Drying, and through chromatography (EA/ hexane) purification of crude product obtaining the solid-state 4-of canescence (5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol 60 (190mg, 62%).LCMS-ESI (m/z) C 22H 24N 2O 4Calculated value: 380.1; Measured value: 381.1[M+H] +, t R=3.45min. 1H NMR (400MHz, CDCl 3) δ 8.02-7.86 (m, 1H), 7.46 (d, J=7.5Hz, 1H), 7.29 (t, J=7.6Hz; 1H), 6.81 (ddd, J=21.0,13.6,5.1Hz, 3H), 5.21 (t; J=5.6Hz, 1H), 4.13 (s, 2H), 4.01 (dq, J=14.1,7.0Hz; 4H), 3.34 (ddd, J=17.5,8.7,4.6Hz, 1H), 3.16-2.92 (m; 1H), and 2.53-2.38 (m, 1H), 1.91 (qdd, J=8.7,6.6; 5.5Hz, 2H), 1.36 (td, J=7.0,4.6Hz, 6H).
2-((4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) amino) ethanol (compound 61)
Figure BPA00001577340400841
Use general program 14 to use 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol 60 and the preparation of 2-ethylaminoethanol.
(2R)-2-((4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) amino) third-1-alcohol (compound 62)
Figure BPA00001577340400842
Use general program 14 by 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol 60 with (R)-the amino third-1-alcohol of 2-prepares.
4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-N-(2-(methyl sulphonyl) ethyl)-2,3-dihydro-1H-indenes-1-amine (compound 63)
Figure BPA00001577340400843
Use general program 14 by 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol 60 and the preparation of 2-(methyl sulphonyl) ethamine.
2-((4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) amino)-N-methyl ethyl sulfonamide (compound 64)
Figure BPA00001577340400844
Use general program 14 by 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-alcohol 60 and 2-amino-N, the preparation of N-dimethyl ethyl sulfonamide.
(R)-N-(4-cyanic acid-2,3-dihydro-1H-indenes-1-subunit)-2-methylpropane-2-sulfenamide (INT-48)
Figure BPA00001577340400851
To 1-oxo-2,3-dihydro-1H-indenes-4-nitrile INT-45 (42.5g, 0.27mol) with (R)-2-methylpropane-2-sulfenamide (36.0g, add in toluene 0.30mol) (530mL) solution purity titanium tetraethoxide (84.1mL, 92.5g, 0.40mol), and at N 2Down at 60 ℃ of following reacting by heating mixture 12h.Rough (R)-N-(4-cyanic acid-2,3-dihydro-1H-indenes-1-subunit)-2-methylpropane-2-sulfenamide INT-48 directly uses in next experiment.LCMS-ESI (m/z) C 14H 16N 2The calculated value of OS: 260.3; Measured value: 261.1[M+H] +, t R=3.19min.
(R)-N-((R)-4-cyanic acid-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide (INT-49)
Figure BPA00001577340400852
At N 2Add THF (1.0L) in the flask of the suspension of rough (R)-N-to comprising (4-cyanic acid-2,3-dihydro-1H-indenes-1-subunit)-2-methylpropane-2-sulfenamide INT-48 down, and reactant mixture is cooled to-78 ℃.In 30min, add in batches sodium borohydride (40.9g, 1.08mol).(internal temperature does not rise in adition process).At-78 ℃ of following stirred reaction mixture 30min, half is 30min outside bath, in 1h, is warming up to 0 ℃ then.0 ℃ reactant mixture is placed ice bath, and with salt solution (100mL) with then with saturated sodium potassium tartrate tetrahydrate (420mL) cancellation, and Ti salt deposition.With EA (1.5L) diluted reaction mixture, and stir overnight at room temperature.The decant organic layer, and use saturated NH successively 4Cl, water and brine wash.Organic layer MgSO 4Drying, and pass through MgSO 4Pad filters.Concentrated filtrate is with rough (R)-N-((R)-4-cyanic acid-2,3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-49 of the brown oily that obtains 52.9g, and it directly is used for next step.LCMS-ESI (m/z) C 14H 18N 2The calculated value of OS: 262.3; Measured value: 263.1[M+H] +, t R=2.99min. 1H NMR (400MHz, CDCl 3) δ 7.89 (d, J=7.7,1H), 7.56 (t, J=6.8; 1H), 7.36 (t, J=7.7,1H), 4.97 (q; J=7.5,1H), 3.50 (d, J=7.6,1H); 3.22 (ddd, J=16.9,8.8,3.9,1H); 3.01 (dt, J=22.4,6.9,1H), 2.70-2.53 (m; 1H), and 2.15-1.95 (m, 1H), 1.33-1.20 (m, 9H).
(R)-and 1-amino-2,3-dihydro-1H-indenes-1-yl)-4-nitrile (INT-50)
Figure BPA00001577340400861
To rough ((R)-N-((R)-4-cyanic acid-2; 3-dihydro-1H-indenes-1-yl)-2-methylpropane-2-sulfenamide INT-49 (52.9g; 0.20mol) MeOH (200mL) solution in add 4N HCl De diox (152.0mL; 30mmol) solution, and at room temperature stir the yellow suspension 1.5h of gained.With MeOH (500mL) dilution crude product mixture, and remove by filter some Ti accessory substances.Concentrated filtrate, and in acetonitrile (500mL) solid of backflow gained.Collect (the R)-1-amino-2 of the white solid of gained, 3-dihydro-1H-indenes-1-yl with generation 13.0g (31%, 3 goes on foot))-4-nitrile hydrochloride INT-50.LCMS-ESI (m/z) C 10H 10N 2Calculated value: 158.2; Measured value: 142.0[M-NH 2] +, t R=0.84min. 1H NMR (400MHz, DMSO) δ 8.61 (s, 3H), 7.96 (d, J=7.7; 1H), 7.83 (d, J=7.5,1H), 7.52 (t; J=7.7,1H), 4.80 (s, 1H), 3.23 (ddd; J=16.6,8.7,5.2,1H), 3.05 (ddd; J=16.6,8.6,6.3,1H); 2.62-2.51 (m, 1H), 2.15-2.01 (m, 1H). 13C?NMR(101MHz，DMSO)δ148.09，141.15，132.48，130.32，127.89，117.27，108.05，54.36，39.08，29.64。Through using 1N NaHCO 3Extraction can prepare free alkali with DCM.LCMS-ESI (m/z) C 10H 10N 2Calculated value: 158.2; Measured value: 142.0[M-NH 2] +, t R=0.83min. 1H NMR (400MHz, CDCl 3) δ 7.52-7.38 (m, 2H), 7.23 (dd, J=17.4,9.8,1H), 4.35 (t, J=7.6,1H), 3.11 (ddd; J=16.8,8.7,3.2,1H), 2.89 (dt, J=16.9,8.5,1H), 2.53 (dddd, J=12.8; 8.1,7.3,3.2,1H), 1.70 (dtd, J=12.8,8.8,8.0,1H). 13C?NMR(101MHz，DMSO)δ150.16，146.67，130.19，128.74，127.38，117.77，107.42，56.86，38.86，29.14。Chirality HPLC: (R)-1-is amino-2,3-dihydro-1H-indenes-1-yl)-5%EtOH in the 4-nitrile use hexane adds 0.05%TEA wash-out: 95%ee, t R=23.02min.
In the first step, use (S)-2-methylpropane-2-sulfenamide preparation (S)-enantiomer INT-51 with similar order (INT-48, INT-49 and INT-50).(S)-t of enantiomer R=20.17min.
(R)-and 4-cyanic acid-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-52)
Figure BPA00001577340400871
Under 0 ℃,, 3-dihydro-1H-indenes-1-yl amino-2) to (R)-1--4-nitrile hydrochloride INT-50 (11.6g, add in DCM 59.6mmol) (100mL) solution TEA (12.0mL, 131.0mmol).In the solution of gained, join Boc acid anhydrides (14.3g, DCM 65.6mmol) (30mL) solution, and stirred reaction mixture 1.5h at room temperature.Reactant mixture brine wash, and organic layer MgSO 4Dry also filtration.Add extra DCM to cumulative volume be 250mL, and add Norit (4.5g).Make product backflow 15min, and make hot mixt pass through diatomite/silica pad filtration.Concentrated filtrate, and in EA (50mL) and hexane (150mL) again crystallization with solid-state (the R)-4-cyanic acid-2 of the canescence that obtains 12.93g (84%), 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-52.LCMS-ESI (m/z) C 15H 18N 2O 2Calculated value: 258.3; Measured value: 281.1[M+Na] +, t R=3.45min.C 15H 18N 2O 2Determination of elemental analysis: C calculated value=69.74%; Measured value=69.98%.H calculated value=7.02%; Measured value=7.14%.N calculated value=10.84%; Measured value=10.89%. 1H?NMR(400MHz，CDCl 3)δ7.64-7.49(m，2H)，7.34(dt，J＝7.7，3.8，1H)，5.36-5.20(m，1H)，4.78(d，J＝6.8，1H)，3.20(ddd，J＝16.9，8.9，3.3，1H)，3.02(dt，J＝25.4，8.4，1H)，2.82-2.53(m，1H)，1.88(dq，J＝13.2，8.6，1H)，1.55-1.44(m，9H)。 13C?NMR(101MHz，DMSO)δ155.52，146.68，146.32，130.89，128.70，127.63，117.51，107.76，77.98，55.09，31.88，29.11，28.19。Chirality HPLC: (R)-4-cyanic acid-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester uses the hexane solution wash-out of 2.5%EtOH:＞99.9%ee, t R=19.36min.
Use (S)-1-amino-2 in a similar fashion, 3-dihydro-1H-indenes-1-yl)-4-nitrile hydrochloride INT-51 preparation (S)-enantiomer INT-53.(S)-t of enantiomer R=28.98min.
(R)-and 4-(N-hydroxy formamidine base)-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-54)
Figure BPA00001577340400872
Use general program 1 preparation.To (R)-4-cyanic acid-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-52 (15.0g, add in EtOH 58.2mmol) (100mL) solution hydroxylamine hydrochloride (12.1g, 174.2mmol) and TEA (17.6mL; 174.2mmol), and at 85 ℃ of following reacting by heating mixture 2h.Remove and desolvate, and the white solid of gained is distributed between water and DCM.Organic layer Na 2SO 4Drying concentrates, and in isopropyl alcohol (50mL), is recrystallized with (the R)-4-(N-hydroxy formamidine base)-2 of the white crystalline solid that obtains 14.4g (85%), 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-54.LCMS-ESI (m/z) C 15H 21N 3O 3Calculated value: 291.4; Measured value: 292.1[M+H] +, t R=2.04min. 1H NMR (400MHz, DMSO) δ 9.53 (s, 1H), 7.38-7.32 (m, 1H), 7.32-7.12 (m; 3H), 5.68 (s, 2H), 4.97 (q, J=8.5,1H); 3.07 (ddd, J=16.6,8.7,2.6,1H); 2.86 (dt, J=16.8,8.4,1H), 2.30 (ddd; J=12.6,7.6,3.6,1H), 1.75 (dq; J=12.3,9.0,1H), 1.44 (s, 9H).
In a similar fashion by (R)-4-cyanic acid-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-53 preparation (S)-4-(N-hydroxy formamidine base)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-55.
(R)-and 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2, the 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester (INT-56)
Figure BPA00001577340400881
Use general program 2 preparations.At room temperature use HOBt (164.8mg, 1.22mmol) and EDC (172.7mg 0.9mmol) handles 2-(3,4-diethoxy phenyl) acetate (150.0mg, DMF 0.67mmol) (3mL) solution.Reaction stirred 2h is until being completed into HOBt-acid compound.Add (R)-4-(N-hydroxy formamidine base)-2, (233.8mg 0.8mmol), and at room temperature stirs 2h to 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-54, and mixture is heated to 80 ℃ of 16h then.Use NaHCO 3(10mL) diluting reaction thing, and with EA extraction (3X10ml).Organic facies MgSO 4Drying, and through chromatography (EA/ hexane) purification of crude product to obtain solid-state (the R)-4-of canescence (5-(3,4-diethoxy benzyl)-1; 2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-56 (187mg; 58%), and directly is used for next step.LCMS-ESI (m/z) C 27H 33N 3O 5Calculated value: 479.2; Measured value: 502.2[M+Na] +, t R=4.11min. 1H NMR (400MHz, CDCl 3) δ 7.91 (d, J=7.6Hz, 1H), 7.39 (d, J=7.5Hz, 1H), 7.27 (t, J=7.7Hz; 1H), 6.81 (ddd, J=20.2,12.8,5.1Hz, 3H), 5.18 (d; J=8.4Hz, 1H), 4.69 (d, J=8.3Hz, 1H), 4.15 (d, J=6.1Hz; 2H), and 4.06-3.93 (m, 4H), 3.32 (ddd, J=17.4,8.8,3.4Hz; 1H), and 3.14-2.91 (m, 1H), 2.65-2.40 (m, 1H), 1.75 (dq, J=12.9; 8.4Hz, 1H), 1.36 (ddd, J=40.2,26.9,22.6Hz, 15H).
In a similar fashion by (R)-4-(N-hydroxy formamidine base)-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-55 preparation (S)-4-(5-(3,4-diethoxy benzyl)-1,2; 4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-57.
(R)-and 4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-amine hydrochlorate (compound 65)
Figure BPA00001577340400891
To (R)-4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2, (150mg 0.312mmol) adds 4N HCl De diox (1mL) solution to 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-56 in De diox (1mL) solution.6h and product deposition at room temperature stir the mixture.Reactant mixture Et 2O dilution, through solid collected by filtration to obtain solid-state (the R)-4-of canescence (5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-amine hydrochlorate 65 (125mg, 96%).LCMS-ESI (m/z): C 22H 25N 3O 3Calculated value: 379.2; Measured value: 402.1[M+Na] +, t R=2.38min. 1H NMR (400MHz, DMSO) δ 8.40 (s, 1H), 8.01 (d, J=7.6Hz, 1H), 7.78 (d; J=7.2Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.02 (d, J=2.0Hz; 1H), 6.90 (dt, J=8.2,5.1Hz, 2H), 4.81 (s, 1H); 4.35 (s, 2H), 4.01 (p, J=6.9Hz, 4H), 3.36 (s, 2H); 3.22-3.04 (m, 1H), 2.55-2.43 (m, 2H), 2.05 (dd, J=14.0; 8.4Hz, 1H), 1.32 (td, J=7.0,4.0Hz, 6H).
Can (5-(3 by (S)-4-in a similar fashion; 4-diethoxy benzyl)-1; 2; 4-oxadiazole-3-yl)-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-57 preparation (S)-4-(5-(3,4-diethoxy benzyl)-1,2; 4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-amine hydrochlorate INT-58.
(R)-2-(t-butyldimethylsilyloxy base) ethyl (4-cyanic acid-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate (INT-59)
Figure BPA00001577340400901
To (R)-4-cyanic acid-2,3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-52 (0.700g, 2.7mmol) middle adding dry DMF (10mL), and at N 2Descend stirred reaction mixture in 0 ℃ ice bath.The adding sodium borohydride (0.541g, 13.5mmol), and the 2h that under 0 ℃, stirs the mixture.Behind 2h, (1.43g 5.9mmol), makes reactant mixture be warming up to room temperature 1h to add (2-bromine oxethyl)-tert-butyl group dimethyl silane.Make reactant be cooled to 0 ℃, and then use saturated NaHCO with MeOH 3Cancellation.Mixture is with EA and salt solution extraction.The organic layer MgSO that merges 4Drying is filtered, and concentrates to obtain brown oil.Through (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-cyanic acid-2,3-dihydro-1H-indenes-1-yl) the t-butyl carbamate INT-59 of flash chromatography on silica gel (20%EA/ hexane) purification of crude product with the yellow oil that obtains 0.868g (77%).LCMS-ESI (m/z) C 23H 36N 2O 3The calculated value of Si: 416.6; Measured value: 317.1[M+H-Boc] +, t R=4.05min. 1H NMR (400MHz, (CD 3) 2SO) δ 7.50 (m, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 5.78 (m, 1H), 4.02 (m, 2H), 3.51 (m, 2H), 3.29 (m, 1H), 2.97 (m, 1H), 2.26 (m, 2H), 1.40 (s, 9H), 0.83 (s, 9H), 0.09 (s, 6H).
(S)-(4-cyanic acid-2,3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate (INT-60)
Figure BPA00001577340400902
With with the similar mode of INT-59 by (S)-4-cyanic acid-2; 3-dihydro-1H-indenes-1-aminocarbamic acid tert-butyl ester INT-53 and 2-chloro-N; N-dimethylacetylamide preparation (S)-(4-cyanic acid-2,3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate INT-60.
(R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(N-hydroxyl-carbonamidine base)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate (INT-61)
Figure BPA00001577340400903
Use general program 1 preparation.To (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-cyanic acid-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-59 (0.800g, add in EtOH 1.9mmol) (8mL) solution hydroxylamine hydrochloride (0.400g, 5.8mmol) and Na 2CO 3(0.610g, 5.8), and at 85 ℃ of following reacting by heating mixture 12h.In case be cooled to room temperature, filter reaction mixture is to use the EtOH flush cake.Concentrated filtrate under reduced pressure, and with EA and brine wash.The organic layer MgSO that merges 4Drying is filtered, and concentrates (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(N-hydroxy formamidine base)-2,3-dihydro-1H-indenes-1-yl) the t-butyl carbamate INT-61 with the light yellow oily that obtains 0.860g (100%).LCMS-ESI (m/z) C 23H 39N 3O 4The calculated value of Si: 449.7; Measured value: 350.2[M+H-Boc] +, t R=1.97min.
(S)-(2-(dimethylamino)-2-oxoethyl) (4-(N-hydroxy formamidine base)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate (INT-62).
Figure BPA00001577340400911
Use general program 1 and with the similar mode of INT-61 by (S)-(4-cyanic acid-2; 3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate INT-60 preparation (S)-(2-(dimethylamino)-2-oxoethyl) (4-(N-hydroxy formamidine base)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-62.
(R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(5-(4-phenyl-5-(trifluoromethyl) thiophene-2-yl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate (INT-63)
Figure BPA00001577340400912
Use general program 2 preparations.At room temperature to 4-phenyl-5-(trifluoromethyl) thiophene-2-carboxylic acid (0.109g, add in DMF 0.4mmol) (3.0mL) solution HOBt (0.088g, 0.57mmol) and EDC (0.109g, 0.57mmol).Stirred reaction mixture 0.5h is until being completed into HOBt-acid compound.Add (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(N-hydroxy formamidine base)-2; 3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-61 (0.200g; 0.44mmol); And the 0.5h that at room temperature stirs the mixture forms intermediate (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(N-(4-phenyl-5-(trifluoromethyl) thiophene-2-ketonic oxygen base) carbonamidine base)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate until observing.At 85 ℃ of following reacting by heating mixture 4h.After cooling, mixture is with DCM and salt solution extraction.The organic layer MgSO that merges 4Drying is filtered and is under reduced pressure concentrated to obtain brown oil.Raw product is through (R)-2-(t-butyldimethylsilyloxy base) ethyl (4-(5-(4-phenyl-5-(trifluoromethyl) thiophene-2-yl)-1 of flash chromatography on silica gel (MeOH/DCM) purifying with the light yellow oil that obtains 0.108g (40%); 2; 4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-63.LCMS-ESI (m/z) C 35H 42F 3N 3O 4The calculated value of SSi: 685.9; Measured value: 411.0[M+H-2-(t-butyldimethylsilyloxy base) ethyl carbamic acid tertiary butyl ester] +, t R=4.01min.
(S)-(4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate (INT-64)
Figure BPA00001577340400921
Use general program 2; With the mode that is similar to INT-63 by (S)-(2-(dimethylamino)-2-oxoethyl) (4-(N-hydroxy formamidine base)-2; 3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-62 and 2-(3; 4-diethoxy phenyl) (S)-((5-(3 for 4-in the acetate preparation; 4-diethoxy benzyl)-1; 2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate INT-64.
(R)-2-(4-(5-(4-phenyl-5-(trifluoromethyl) thiophene-2-yl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-base is amino) ethanol (compound 67)
Figure BPA00001577340400922
(R)-2-in being dissolved in DCM (1.5mL) (t-butyldimethylsilyloxy base) ethyl (4-(5-(4-phenyl-5-(trifluoromethyl) thiophene-2-yl)-1; 2; 4-oxadiazole-3-yl)-2; 3-dihydro-1H-indenes-1-yl) t-butyl carbamate INT-63 (0.108g; 0.16mmol) in add 2N HCl ethereal solution (1.45mL, 2.9mmol).Agitating solution 12h at room temperature.Flow down to remove at nitrogen and desolvate, and under vacuum desciccate with the hydrochloride of (R)-2-(4-(5-(4-phenyl-5-(trifluoromethyl) thiophene-2-yl)-1,2,4-oxadiazole-3-yl)-2, the basic amino of 3-dihydro-1H-indenes-1-) ethanol 67 of obtaining 0.052g (65%).LCMS-ESI (m/z): C 24H 20F 3N 3O 2The calculated value of S: 471.5; Measured value: 472.1[M+H] +, t R=7.43min (method 2). 1H?NMR(400MHz，CDCl 3)δ9.62(s，1H)，8.19(d，J＝7.6，1H)，8.03(d，J＝7.5，1H)，7.87(t，J＝1.5，1H)，7.53-7.40(m，6H)，4.86(d，J＝4.8，1H)，3.88(s，2H)，3.74-3.50(m，1H)，3.41(ddd，J＝13.3，9.4，4.4，1H)，3.06(m，1H)，2.98(m，1H)，2.67-2.42(m，2H)。 13C?NMR(100MHz，DMSO)δ169.22，168.07，145.68，144.75，139.39，135.43，132.42，129.42，129.37，129.25，128.69，128.27，127.62，126.41，123.16，122.37，120.47，61.10，56.63，46.54，31.66，27.80。
(S)-2-((4-(5-(3,4-diethoxy benzyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) amino)-N,N-dimethylacetamide (compound 66)
Figure BPA00001577340400931
With with compound 67 similar modes by (S)-((5-(3 for 4-; 4-diethoxy benzyl)-1; 2; 4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) (2-(dimethylamino)-2-oxoethyl) t-butyl carbamate INT-64 preparation (S)-2-((4-(5-(3,4-diethoxy benzyl)-1; 2; 4-oxadiazole-3-yl)-2,3-dihydro-1H-indenes-1-yl) amino)-N,N-dimethylacetamide 66.
5-cyano-1 H-indol--1-carboxylic acid tert-butyl ester (INT-65)
Figure BPA00001577340400932
To comprising 5-cyanoindole (500mg, CH 3.52mmol) 3Add Boc in CN (5mL) solution 2O (920mg, 4.22mmol) and DMAP (42mg, 0.35mmol), and the 0.5h that at room temperature stirs the mixture.Enriched mixture is dissolved among the DCM it again, and through the 5-cyano-1 H-indol--1-carboxylic acid tert-butyl ester INT-65 of chromatography (EtOAc/ hexane) with the white solid state that obtains 766mg (90%).LCMS-ESI (m/z) C 14H 14N 2O 2Calculated value: 242.27; Measured value: 243.1[M+H] +, t R=3.93min.
5-(N-hydroxy formamidine base)-1H-indoles-1-carboxylic acid tert-butyl ester (INT-66)
Figure BPA00001577340400933
Use general program 1 preparation.To comprise 5-cyano-1 H-indol--1-carboxylic acid tert-butyl ester INT-65 (200mg, add in flask 0.73mmol) EtOH (6mL), hydroxylamine hydrochloride (177mg, 2.54mmol) and Na 2CO 3(154mg, 1.45mmol).Under 75 ℃, stir the mixture and spend the night, concentrate then, it is dissolved among the DCM again, and uses NaHCO 3Washing.The organic layer Na that merges 2SO 4Drying, and concentrate rough white solid 5-(N-hydroxy formamidine base)-1H-indoles-1-carboxylic acid tert-butyl ester INT-66 to obtain 222mg, it directly is used for next experiment.LCMS-ESI (m/z) C 14H 17N 3O 3Calculated value: 275.3; Measured value: 276.1[M+H] +, t R=2.25min.
5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-yl)-1H-indoles-1-carboxylic acid tert-butyl ester (INT-67)
Use general program 2 preparations.N at room temperature, 2Stir under the atmosphere comprise 3-cyanic acid-4-isopropoxy benzoic acid (135mg, 0.66mmol), HOBt (130mg, 0.85mmol) and EDC (164mg, the flask 1.5h of DMF 0.85mmol) (2.5mL) solution.(199mg, DMF 0.72mmol) (2.5mL) solution joins in the mixture with rough 5-(N-hydroxy formamidine base)-1H-indoles-1-carboxylic acid tert-butyl ester INT-66.At room temperature behind the 1h, mixture is heated to 75 ℃, and stir overnight.Use NaHCO 3Diluted reaction mixture, and extract with EtOAc.The organic extract liquid Na that merges 2SO 4Drying, and concentrate.The crude material of gained is through 5-(5-(3-cyanic acid-4-isopropyl phenyl)-1,2,4-oxadiazole-3-the yl)-1H-indoles-1-carboxylic acid tert-butyl ester INT-67 of chromatography (EtOAc/ hexane) to obtain 174mg (59%) white solid state.LCMS-ESI (m/z) C 25H 24N 4O 4Calculated value: 444.5; Measured value: 445.1[M+H] +, t R=3.67min (method 1).
5-(3-(1H-indoles-5-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (compound 68)
To comprising 5-(5-(3-cyanic acid-4-isopropyl phenyl)-1; 2,4-oxadiazole-3-yl)-(75mg adds diox (2mL) to 1H-indoles-1-carboxylic acid tert-butyl ester INT-67 in flask 0.17mmol); Then add 4N HCl De diox (0.5mL, 2mmol) solution.At room temperature stirred reaction mixture spends the night, then 50 ℃ of following heated overnight.Add extra 4N HCl/ diox (0.5mL, 2mmol), under 50 ℃ again heating blends 2h to accomplish deprotection.Reactant mixture dilutes with EtOAc, and uses NaHCO 3Washing.The organic layer brine wash that merges is used Na 2SO 4Drying, and concentrate.Said material is through 5-(3-(1H-indoles-5-yl)-1,2,4-oxadiazole-5-the yl)-2-isopropoxy benzonitrile 68 of chromatography (EtOAc/ hexane) purifying with the white solid state that obtains 17mg (30%).LCMS-ESI (m/z) C 20H 16N 4O 2Calculated value: 344.5; Measured value: 345.1[M+H] +, t R=2.34min (method 1). 1H?NMR(400MHz，CDCl 3)δ8.51-8.47(m，1H)，8.45(d，J＝2.2Hz，1H)，8.38(d，J＝7.2Hz，1H)，8.35(dd，J＝8.9，2.2Hz，1H)，7.99(dd，J＝8.5，1.6Hz，1H)，7.51(d，J＝8.5Hz，1H)，7.33-7.28(m，1H)，7.11(d，J＝9.0Hz，1H)，6.72-6.64(m，1H)，4.79(dt，J＝12.2，6.1Hz，1H)，1.47(t，J＝5.8Hz，6H)。
N-hydroxyl benzofuran-5-carbonamidine (INT-68)
Figure BPA00001577340400951
Use general program 1 preparation.To comprise benzofuran-5-benzonitrile (200mg, add in flask 0.73mmol) EtOH (6mL), hydroxylamine hydrochloride (176.7mg, 2.54mmol) and Na 2CO 3(154mg, 1.42mmol).Under 75 ℃, stir the mixture and spend the night, concentrate then, it is dissolved among the DCM again, and uses NaHCO 3Washing.The organic layer Na that merges 2SO 4Drying, and concentrate to obtain rough white solid N-hydroxyl benzofuran-5-carbonamidine INT-68 of 222mg, it directly is used for next step and need not purifying.LCMS-ESI (m/z) C 9H 8N 2O 2Calculated value: 176.2; Measured value: 177.1[M+H] +, t R=0.83min.
5-(3-(benzofuran-5-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile (compound 69)
Figure BPA00001577340400952
Use general program 2 preparations.N at room temperature, 2Stir under the atmosphere comprise 3-cyanic acid-4-isopropoxy benzoic acid (147.7mg, 0.72mmol), HOBt (143mg, 0.94mmol) and EDC (180mg, the flask 0.5h of DMF 0.94mmol) (2.0mL) solution.(218mg, DMF 0.79mmol) (2.0mL) solution joins in the mixture with N-hydroxyl benzofuran-5-carbonamidine INT-68.At room temperature behind the 1h, under 85 ℃, stir the mixture and spend the night.Use NaHCO 3Diluted reaction mixture, and extract with EA.The organic extract liquid Na that merges 2SO 4Drying, and concentrate.The crude material of gained is carried out 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazole-5-the yl)-2-isopropoxy benzonitrile 69 of chromatography (EA/ hexane) with the white solid state that obtains 110mg (44%).LCMS-ESI (m/z) C 20H 15N 3O 3Calculated value: 345.4; Measured value: 346.1[M+H] +, t R=2.77min (method 1). 1H?NMR(400MHz，CDCl 3)δ8.45(dd，J＝4.5，1.9Hz，2H)，8.35(dd，J＝8.9，2.2Hz，1H)，8.12(dd，J＝8.6，1.7Hz，1H)，7.71(d，J＝2.2Hz，1H)，7.63(d，J＝8.6Hz，1H)，7.13(d，J＝9.0Hz，1H)，6.88(dd，J＝2.2，0.8Hz，1H)，4.80(s，1H)，1.48(d，J＝6.1Hz，6H)。
The different cigarette carbonamidine of N-hydroxy-3-methyl (isonicotinimidamide) (INT-69)
Figure BPA00001577340400961
Use general program 1 preparation.To the different cigarette nitrile of 3-methyl (0.500g, add in EtOH 4.2mmol) (7mL) solution hydroxylamine hydrochloride (0.588g, 8.5mmol) and Na 2CO 3(1.34g, 12.7mmol), at 85 ℃ of following reacting by heating mixture 4h.In case be cooled to room temperature, filter reaction mixture is used the EtOH flush cake.Concentrated filtrate under reduced pressure.The light yellow solid of gained grinds with frozen water (50mL), filter, and solid washs with frozen water (5mL).The drying under reduced pressure solid is to obtain the different cigarette carbonamidine of the N-hydroxy-3-methyl INT-69 of 0.47g (74%) white powder.LCMS-ESI (m/z) C 7H 9N 3The calculated value of O: 151.2; Measured value: 152.1[M+H] +, t R=0.56min. 1H NMR (400MHz, CD 3OD) δ 8.43-8.32 (m, 2H), 7.34 (d, J=5.0,1H), 2.39 (s, 3H).
2-isopropoxy-5-(3-(3-picoline-4-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (compound 70)
Figure BPA00001577340400962
Use general program 2 preparations.At room temperature to 3-cyanic acid-4-isopropoxy benzoic acid (0.122g, add in DMF 0.60mmol) (1.5mL) solution HOBt (0.132g, 0.86mmol) and EDC (0.165g, 0.86mmol).Reaction stirred 0.5h is until being completed into HOBt-acid compound.(0.100g, 0.66mmol), and the 0.5h that at room temperature stirs the mixture is until the formation of observing intermediate N (3-cyanic acid-4-isopropoxy benzoyloxy)-different cigarette carbonamidine of 3-methyl to add the different cigarette carbonamidine of N-hydroxy-3-methyl INT-69.Then, at 80 ℃ of following reacting by heating mixture 4h.After cooling, mixture is with DCM and salt solution extraction.The organic layer MgSO that merges 4Drying is filtered and is under reduced pressure concentrated to obtain brown oil.Raw product is recrystallized in MeOH (3mL), and filters the crystal of gained and wash to obtain the solid-state product of white crystal with cold MeOH.In product, add Et 2O (0.5mL) then adds the Et of 2N HCl 2O (0.6mL) solution.At room temperature stirred the mixture 10 minutes, then at N 2Following dry, then dry hydrochloride under vacuum with 2-isopropoxy-5-(3-(3-picoline-4-yl)-1,2,4-oxadiazole-5-yl) benzonitrile 70 of obtaining 0.087g (45%).LCMS-ESI (m/z) C 18H 16N 4O 2Calculated value: 320.3; Measured value: 321.1[M+H] +, t R=8.82min (method 2). 1H?NMR(400MHz，CDCl 3)δ8.80(d，J＝17.5，2H)，8.70(d，J＝5.7，1H)，8.44(d，J＝2.2，1H)，8.36(dd，J＝8.9，2.2，1H)，7.18(d，J＝9.1，1H)，4.83(dt，J＝12.2，6.1，1H)，2.95(s，3H)，1.49(d，J＝6.1，6H)。 13C?NMR(101MHz，DMSO)δ173.90，166.58，162.81，147.11，142.99，137.55，135.01，134.79，134.06，125.00，115.42，115.17，115.00，102.57，72.66，21.48，18.69。
4-bromo-2-((t-butyldimethylsilyloxy base) methyl) pyridine (INT-70)
To (4-bromopyridine-2-yl) methyl alcohol that stirs (1.50g, DCM 8.0mmol) (4mL) solution adding tertiary butyl chloride dimethyl silane (1.20g, 8.0mmol), then add TEA (1.60g, 12.0mmol).Reactant mixture was at room temperature stirred 12 hours, then with salt solution and EA washing.The organic layer MgSO that merges 4Drying is filtered and is concentrated to obtain amber liquid.Raw product is through 4-bromo-2-((t-butyldimethylsilyloxy base) methyl) the pyridine INT-70 of chromatography (EA/ hexane) purifying with the light yellow liquid that obtains 1.67g (70%).LCMS-ESI (m/z) C 12H 20The calculated value of BrNOSi: 302.3; Measured value: 303.0[M+H] +, t R=4.87min (method 1). 1H?NMR(400MHz，CDCl 3)δ8.30(d，J＝5.3，1H)，7.68(dd，J＝1.9，0.7，1H)，7.35-7.24(m，1H)，4.80(s，2H)，0.99-0.86(m，9H)，0.16-0.06(m，6H)。
2-((t-butyldimethylsilyloxy base) methyl) different cigarette nitrile (INT-71)
Figure BPA00001577340400972
To 4-bromo-2-((t-butyldimethylsilyloxy base) methyl) pyridine INT-70 (0.800g that stirs; 2.6mmol) 3mL 1-methyl-2-pyrrolidines (NMP) solution in add zinc cyanide (0.610g; 5.2mmol) and tetrakis triphenylphosphine palladium (0) (0.060g, 0.052mmol).Use N 2Make the solution degasification, and at 95 ℃ of following reacting by heating mixture 12h.After cooling, with the saturated NaHCO of reactant mixture 3Dilute, and extract with DCM.The organic layer Na that merges 4SO 4Drying is filtered and is concentrated.Raw product is through light yellow solid-state 2-((t-butyldimethylsilyloxy base) methyl) the different cigarette nitrile INT-71 of chromatography (MeOH/DCM) purifying to obtain 0.170g (26%).LCMS-ESI (m/z) C 13H 20N 2The calculated value of OSi: 248.4; Measured value: 249.1[M+H] +, t R=4.21min (method 1).
2-((t-butyldimethylsilyloxy base) the methyl)-different cigarette carbonamidine of N-hydroxyl (INT-72).
Use general program 1 preparation.To the different cigarette nitrile INT-71 of 2-((t-butyldimethylsilyloxy base) methyl) (0.169g, add in EtOH 0.68mmol) (8mL) solution hydroxylamine hydrochloride (0.142g, 2.0mmol) and Na 2CO 3(0.216g, 2.0mmol), and at 85 ℃ of following reacting by heating mixture 12h.In case be cooled to room temperature, filter reaction mixture is used the EtOH flush cake.Concentrated filtrate under reduced pressure, and with EA and brine wash.The organic layer MgSO that merges 4Drying is filtered, and concentrates 2-((t-butyldimethylsilyloxy base) the methyl)-different cigarette carbonamidine of the N-hydroxyl INT-72 with the light yellow oily that obtains 0.191g (100%).LCMS-ESI (m/z) C 13H 23N 3O 2The calculated value of Si: 281.4; Measured value: 282.1[M+H] +, t R=2.76min (method 1). 1H?NMR(400MHz，(CD 3) 2SO)δ8.50(dd，J＝5.2，0.7，1H)，7.74(dd，J＝1.6，0.7，1H)，7.51(dd，J＝5.2，1.7，1H)，5.98(s，2H)，0.96-0.89(m，9H)，0.14-0.07(m，6H)。
5-(3-(2-(hydroxymethyl) pyrrole fixed-4-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy-benzonitrile (compound 71)
Figure BPA00001577340400982
Use general program 2 preparations.At room temperature to 3-cyanic acid-4-isopropoxy benzoic acid (0.033g, add in DMF 0.16mmol) (1.0mL) solution HOBt (0.036g, 0.23mmol) and EDC (0.045g, 0.23mmol).Reaction stirred 0.5h is until being completed into HOBt-acid compound.Add 2-((t-butyldimethylsilyloxy base) the methyl)-different cigarette carbonamidine of N-hydroxyl INT-72 (0.050g; 0.18mmol), and the 0.5h that at room temperature stirs the mixture is until the formation of observing intermediate 2-((t-butyldimethylsilyloxy base) methyl)-different cigarette carbonamidine of N-(3-cyanic acid-4-isopropoxy benzoyloxy).At 85 ℃ of following reacting by heating mixture 4h.In the reactant mixture of cooling, add MeOH (1.0mL), and filtering solution.Gained filtrating is through the tfa salt 71 of preparation HPLC purifying with 5-(3-(2-(hydroxymethyl) pyridin-4-yl)-1,2,4-oxadiazole-5-yl)-2-isopropoxy benzonitrile of obtaining 5.6mg (8%).LCMS-ESI (m/z) C 18H 16N 4O 3Calculated value: 336.3; Measured value: 337.1[M+H] +, t R=7.45min (method 2). 1H?NMR(400MHz，CD 3OD)δ8.78(d，J＝5.5，1H)，8.48(dd，J＝10.6，8.3，1.4，3H)，8.23(dd，J＝5.5，1.6，1H)，7.48(d，J＝9.0，1H)，4.93(s，2H)，4.89(m，1H)，1.48(d，J＝6.1，6H)。
The compound of selecting is shown in Table 1 with their corresponding data of analyzing, and wherein LCMS data method for using 2 (referring to universal method) is gathered.Measure the enantiomeric purity of key intermediate and selected final compound, and infer enantiomeric purity from synthesizing for other compound.
Table 1
Figure BPA00001577340400991
Figure BPA00001577340401001
Figure BPA00001577340401011
Figure BPA00001577340401021
Figure BPA00001577340401031
Figure BPA00001577340401041
Figure BPA00001577340401051
Figure BPA00001577340401081
Figure BPA00001577340401091
Figure BPA00001577340401101
Figure BPA00001577340401111
Figure BPA00001577340401121
Figure BPA00001577340401131
Biologicall test
The mensuration program
S1P 1The analysis that the cAMP Report Body inhibitory action of-mediation produces
The mammal expression plasmid that comprises the S1P1/EDG1 of being cloned among the pcDNA3.1 is available from Missouri S&T cDNA resource center (Missouri S&T cDNA Resource Centre).Human S1P 1The nucleotide of/EDG1 and amino acid sequence Hla and Maciag (J Biol Chem, 265 (1990), open in 9308-9313).With standard technique with S1P 1/ pcDNA3.1 transfection and is selected stable single cell clone to CRE-bla CHO K1 (Invitrogen) cell-line.Pass through S1P 1The cell surface FACS of antibody (R&D system, clone number 218713) induces the inhibition of cAMP to confirm functional S1P with the Forskolin that S1P mediates 1/ EDG1 receptor expression.
S1P 1CRE-bla CHOK1 Report Body analysis-S1P 1The sign of activator
With 10 4Individual cells/well/19.5 μ l analyze medium, and (DMEM-does not have phenol, the serum that 0.5% active carbon/glucan is handled, 2mM glutamine; 0.1mM NEAA; The 1mM Sodium Pyruvate, 25mM Hepes) seed cells in 384 hole black wall/dianegatives, and at 37 ℃ of following 5%CO 2In hatched 18 hours.At 10mM Hepes, 0.1% Pluronic F127 produces dose-effect curve (10 point) in the presence of Forskolin.Under 37 ℃ in the presence of 2 μ M Forskolins, with the compound treatment cell of 0.5 μ l 4 hours.Explanation according to producer prepares the beta-lactamase fluorogenic substrate (LiveBLAzer based on FRET TM-FRET B/G Loading Kit CC4-AM; Invitrogen), and at room temperature incubated cell is 2 hours.On Ex:410/Em:458 and Ex:410/Em:522, read plate, and measure responsiveness (response ratio).Through the EC of nonlinear regression analysis data with the inhibition of confirming the cAMP that Forskolin is induced 50
The specificity of relative other S1P acceptor
For measuring the specificity of compound, use following cell-line: S1P to other S1P acceptor 2CRE-bla CHOK1, S1P 3-G α 15 NFAT-bla HEK293T (Invitrogen), S1P 4-bla TANGO U2OS (Invitrogen), S1P 5-bla TANGO U2OS (Invitrogen).Use for S1P 1Identical mensuration setting, but it does not contain Forskolin.S1P 4And S1P 5Analysis is expressed in the medium (Invitrogen) at FreeStyle and is carried out.With S1P 5Cell was hatched 48 hours, afterwards with this cell of compound treatment.
The S1P of report 1Active
The S1P that selects 1The activity data of activator is shown in Table 2.Field of activity is represented as follows: ++ ++ expression agonist activity＜0.05nM, +++represent agonist activity between 0.05 to 0.50nM, and ++ represent agonist activity between 0.50 to 5.00nM, and+expression agonist activity＞5.00nM.N/A representes not provide.
Table 2
Figure BPA00001577340401141
Figure BPA00001577340401151
The S1P of particular compound 1-S1P 5Data are shown in Table 3.Activator value (EC 50) represent with nM.
Table 3
Compound number S1P 1 ?S1P 2 ?S1P 3 ?S1P 4 S1P 5
8 0.143 ?＞10000 ?＞10000 ?＞10000 108.9
13 0.100 ?＞10000 ?＞10000 ?＞10000 77.0
29 0.065 ?＞10000 ?＞10000 ?＞10000 37.8
33 0.192 ?＞10000 ?＞10000 ?616.7 260.1
37 0.024 ?1437 ?＞10000 ?879.4 3.5
49 0.104 ?＞10000 ?＞10000 ?＞10000 94.6
Measure in the body
The mensuration of absolute oral administration biaavailability in the rat
Pharmacokinetic is to carry out in the female Sprague-Dawely rat (Simonsen Laboratories or Harlan Laboratories) in non-fasting.Rat feeding is in the mechanism of ALAAC approval and this research has obtained management of laboratory animal and the use committee (IACUC) ratifies.Animal adapts to 48 hours at least before the experiment beginning in the laboratory.
Compound is with 5%DMSO/5% polysorbas20 and 90% purified water (venoclysis) or 5%DMSO/5% polysorbas20 and 90%0.1N HCL (per os is raised by force) preparation.Confirm for the concentration of drug solns through HPLC-UV.For intravenous administration, with compound through infusion pump at one minute with interior administration (n=4 rat/compound) in the jugular vein of manual work restriction animal.Oral administration is to irritate the stomach pin with the stainless steel of standard to carry out (n=2-4 rat/compound) through raising by force.For these two kinds of methods of administration, gather the blood of eight time points after the administration, last sample is collection in 24 hours after administration.Aliquot in the blood sample transferred in polypropylene 96 orifice plates and freezing up to analysis down at-20 ℃.
After blood sample at room temperature thawed, in each hole, add 5 μ L DMSO.Comprise the 150 μ L acetonitrile precipitation protein of marking (4-hydroxyl-3-(α-imines benzyl)-1-methyl-6-phenylpyridine-2-(1H)-ketone) and 0.1% formic acid in the 200nM through adding.On oscillator plate, plate is mixed 1 minute to promote protein precipitation, then with 3,000rpm made protein agglomerating in centrifugal 10 minutes.Before LC/MS/MS analyzes, supernatant is transferred in the flat board of cleaning and with 3, centrifugal 10 minutes of 000rpm is so that any remaining solid matter is agglomerating.Process the calibration curve standard through being present in the EDTA rat blood that 5 μ L compounds among the DMSO mix fresh collection.Each wheel biology-analysis comprises 8 calibration curves crossing over 5nM to 10000nM scope.Standard items and rat pharmacokinetics sample are likewise handled.
Concentration in the rat pharmacokinetics sample is to use the standardized HPLC-LC/MS/MS method of relative 8 calibration curves to measure.Said system is made up of Leap CTC Pal syringe, Agilent 1200 HPLC that have with the binary pump of Applied Biosystems 3200 QTrap couplings.Compound has chromatography on the Phenomenex Synergy Fusion RP 20x2mm 2um Mercury Cartridge of safeguard protection.Gradient method uses mobile phase A of being made up of the water that contains 0.1% formic acid and the Mobile phase B of being made up of the acetonitrile that contains 0.1% formic acid, 0.7 to the 0.8mL/min flow velocity that changes.Use electron spray ionisation (ESI) interface to produce ion with positive ion mode.Exploitation is to multiple-reaction monitoring (MRM) method of each compound.The hot type atomizer is arranged on 325 ℃, has the atomizer electric current of 4.8 μ A.The collision energy range that is used to produce daughter ion is between 29 to 39V.The peak area ratio that the MRM that changes from the specific quality of all cpds obtains is used to quantitatively.The quantitation limit of this method is generally 5nM.1.4.2 gathers and analyzes data with the Analyst software version.
With non-atrioventricular method (WinNonlin version 5.2; The model 202 that is used for the model 200 of oral administration and is used for venoclysis) comes analyzing blood and/or plasma concentration data to the time.Use following expression formula to calculate absolute oral administration biaavailability (%): (oral AUC * IV dosage)/(IV AUC * oral dose) * 100.
Lymphocyte reduces
In mouse: female C57BL6 mouse (Simonsen Laboratories, Gilroy CA) is raised in the mechanism of ALAAC approval and this research has obtained management of laboratory animal and the use committee (IACUC) approval.Animal adapts to 5 days at least before the experiment beginning in the laboratory.Raise by force to mouse administration (n=3/ compound/time point) through using the 1mg/kg compound per os of preparing in the media of forming by 5%DMSO/5% polysorbas20 and 90%0.1N HCl.Control mice is with media PO administration.Gather the tip whole blood sample from the mouse of isoflurane anesthesia to EDTA through cardiac puncture.With rat anti-mouse CD16/CD32 (Mouse BD Fc Block, #553141), PE-rat anti-mouse CD45R/B220 (BD #553089), APC-Cy7-rat anti-mouse CD8a (BD#557654) and Alexa Fluor647-rat anti-mouse CD4 (BD #557681) hatch whole blood 30min on ice.With BD Pharm Lyse Lysing buffer solution (#555899) lysed erythrocyte and through the facs analysis leucocyte.Lymphocyte reduces the leukocytic percentage that is expressed as CD4 or CD8 positive T cell.Reduce response through then calculate the whole lymphocyte that area was estimated in 24 hours under the effect curve (AUEC) with linear trapezoid method.
In rat: female rats (Simonsen Laboratories, Gilroy CA) is raised in the mechanism of ALAAC approval and this research has obtained management of laboratory animal and the use committee (IACUC) approval.Animal adapts to 5 days at least before the experiment beginning in the laboratory.1mg/kg compound per os through using the media preparation of being made up of 5%DMSO/5% polysorbas20 and 90%0.1N HCl raises by force to rat administration (n=3/ compound/time point).Control rats is with media PO administration.From the mouse of isoflurane anesthesia through eye after hole take whole blood and gather terminal sample to EDTA through cardiac puncture.Hatch whole blood on ice 30 minutes with mouse anti rat CD32 (BD #550271), PE-mouse anti rat CD45R/B220 (BD #554881), PECy5-mouse anti rat CD4 (BD#554839) and APC-mouse anti rat CD8a (eBioscience #17-0084).Use BD Pharm Lyse Lysing buffer solution (#555899) lysed erythrocyte and analyze leucocyte through BD FACSArray.Lymphocyte reduces the leukocytic percentage that is expressed as CD4 or CD8 positive T cell.Reduce response through then calculate the whole lymphocyte that area was estimated in 24 hours under the effect curve (AUEC) with linear trapezoid method.In some experiment, use the animal blood analyzer based on impedance (IDEXX Preclinical Research Services, Sacramento, CA) numeration of mensuration total lymphocyte of standard.
The assessment of the therapeutic index of rat
Can in the male and female Sprague-Dawely rat (Simonsen Laboratories) of non-fasting, study.Rat can be raised in the mechanism of AAALAC approval and this research can obtain management of laboratory animal and the use committee (IACUC) approval.Animal should adapt to 5 days at least before the experiment beginning in the laboratory.
Compound can be mixed with the suspension in the media of being made up of 0.5% carboxymethyl cellulose in the purified water (Acros Organics) (with hydrochloric acid with pH regulator to～2.2).Identical preparation is used in the lymphocyte minimizing and toxicologic study as described below of rat.In the suspension each compound concentrations should through HPLC-UV confirm aimed concn ± 10% scope in.
Before carrying out toxicologic study, can measure the effect (with reference to the measuring method of above-mentioned rat medium size lymphocyte minimizing) of 3-5 days daily doses of all cpds to the periphery T cell counting of female rats.In the research that these lymphocytes reduce, behind final research dosage, blood sample is collected on the EDTA by certain interval.Yan Jiu acquisition time not necessarily must be identical each time, yet all research can comprise the sample of gathering in 24 hours after the last administration.The data that lymphocyte reduces are used as biomarker and think that follow-up toxicologic study selection equates the dosage of pharmacological activity.The rat that the low dosage of toxicologic study is handled with respect to media for 24h after final administration causes the dosage of each compound of T-cell counting decline 50%.
In toxicologic study, use randomization based on body weight to distribute three male and three female rats in the administration group.Control group in each research is accepted media.All animals are raised administration in continuous 5 or 14 days with 5mL/kg/ days dose volume by force through per os.Observe the performance of any bad reaction of animal every day.After after the final research administration 24 hours, with the isoflurane anesthesia rat and through intracardiac puncture obtain that the peripheral blood sample is used for hematology and clinical chemistry assess (IDEXX Laboratories, Sacramento, CA).Gather, weigh the band tracheae lung and be used for then preparing histologic analysis through the tracheae perfusion with the formalin of 10% neutral buffered.The lung that to fix internally is kept in the formalin of 10% neutral buffered and sacrificial meat histological inspection (IDEXX) then.
Can assess the dosage of each compound that causes lung and final body anharmonic ratio rate increase by 10% of each compound through linear interpolation method.Therapeutic index can be evaluated as the ratio that produces 10% lung weight dosage that increases and the dosage that produces 50%T cell exhaustion then.
The description of TNBS Crow engler's colitis model in the rat
Male Sprague-Dawley (180-200 gram) is adapted to 7 days, specify every group of 8 rats then so that every group has approximately identical average weight.Begin before 24 hours, rat fasting in disease.Anesthetized rat and weighing are inculcated 80mg/kg TNBS solution (50%TNBS:50%200 standard ethanol (proof ethanol)) through the 20 gram feeding pins that insert anus then in colon.Rat keeps a low level until from anesthesia, restoring.TBBS-inculcates beginning oral administration every day after two hours, continues six days.Prednisolone is as positive control and with 10mg/kg oral administration every day.Monitored every day after body weight and the administration in the end 24 hours, and put to death all treated animals.Take out colon, the flushing fecal matter, inspection comprises the overall change of narrow, adhesion and ulcer then.The weight that length, the far-end of record colon is 2 centimetres and the thickness of intestines wall.
The description of Flu-A H1N1 model in the mouse
Male C57Bl/6 (6-8 age in week) can be adapted to 7 days, distribute every group of 5-8 mouse then so that every group has approximately identical average weight.Can use 10 4PFUs mouse adaptability influenza A virus (A/WSN/33) approach infecting mouse in tracheae.After infecting back 1 hour, can use 0.2-1.5mg/kg compound per os to handle mouse.After infecting back 48 hours, mouse can be implemented painless deadly art through cervical dislocation, and can gather BAL fluid.Can carry out quantitative cytokine analysis through ELISA.In some experiments, can carry out whole health perfusion, and can collect the cell counting that lung is used for inflammatory cell.Through with 3-10 * 10 4PFU mouse adaptability influenza a virus infection 14 days with on carry out life search.

Claims (60)

1. compound with structure of formula I-R or I-S, or its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate:
Figure FPA00001577340300011
Wherein,
X is-NR ' R " or-OR " ';
Y is-CN ,-Cl ,-CF 3, I ,-COOH or-COOR 1
R ' is H, C 1-4Alkyl, primary hydroxyl C 1-4Alkyl ,-SO 2-R 1Or-CO-R 1
R " be H ,-SO 2-R 3, randomly by one or more R 2Substituted C 1-4Alkyl is perhaps randomly by R 4Substituted loop section, wherein this ring portion is divided into piperidyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazole radicals or phenyl;
Perhaps; R ' and R " nitrogen-atoms that is connected with them forms and contains 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic; wherein this extra hetero atom is O or N, and wherein this heterocycle is independently selected from randomly that following substituting group list replaces or is polysubstituted :-OH, oxo ,-NH 2, primary hydroxyl-C 1-4Alkyl ,-COOH ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1,-N (R 1R 1) and-(CH 2) m-CO-N (R 5R 5);
R " ' be H, C 1-4Alkyl or-CO-R 1
Each R 1Be C independently 1-4Alkyl or H;
Each R 2Be independently H, halogen, OH, oxo ,=NH, NH 2,-COOH, F ,-NHR 1-N (R 5R 5) ,-SO 2-R 1,-SO 2-N (R 5R 5) ,-N (R 1)-SO 2-R 1,-COOR 1,-OCO-R 1,-CO-N (R 5R 5) ,-N (R 1)-COR 1, C 1-3Alkyl, C 1-3Alkoxyl and randomly by R 4Substituted loop section; Wherein, this ring portion is divided into piperazinyl, piperidyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazole radicals, benzimidazolyl, azetidinyl, cyclobutinyl or phenyl;
Each R 3Be R independently 2, C 1-4Alkyl, C 3-6Cycloalkyl or randomly by one or more R 2Substituted C 1-4Alkyl;
Each R 4Be independently halogen, OH ,-NH 2,-NHR 1,-N (R 1R 1) ,-COOH ,-COOR 1,-NHCO-R 1Each R 5Be C independently 1-4Alkyl or H, perhaps two R 5The nitrogen-atoms that connects with their forms and contains 0 or 1 extra heteroatomic 4,5 or 6 yuan of saturated heterocyclic, and wherein, this extra hetero atom is O or N, wherein this heterocycle randomly by-OH ,-NH 2,-N (R 1R 1), primary hydroxyl C 1-4Alkyl ,-(CH 2) m-COOH ,-(CH 2) m-COOR 1Replace; And
Each m is 0,1,2 or 3 independently.
2. compound according to claim 1, wherein, said compound has general formula I-R, or the structure of its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
3. compound according to claim 1, wherein, said compound has general formula I-S, or the structure of its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
4. according to the described compound of claim 1-3, wherein, said compound is that basic optical is pure.
5. according to the described compound of claim 1-4; Wherein, As with as described in after the administration of compound 5 or 14 days at the rat in-vivo measurement; Said compound has and is at least 5 therapeutic index, and wherein said therapeutic index is less than or equal to the ratio of 10% dosage and the dosage of realizing 50% lymphocyte minimizing for when finishing in said 5 or 14 days, realizing lung and the increase of whole opisthosoma anharmonic ratio.
6. compound according to claim 5, wherein, said therapeutic index is at least 10.
7. compound according to claim 5, wherein, said therapeutic index is at least 20.
8. according to the described compound of claim 5-7, wherein, the therapeutic index of said compound is greater than the therapeutic index of the enantiomer of said compound.
9. compound according to claim 8, wherein, the therapeutic index of said compound be said compound enantiomer therapeutic index at least 150%.
10. according to the described compound of claim 1-9, wherein, Y is Cl.
11. according to the described compound of claim 1-9, wherein, Y is CF 3
12. according to the described compound of claim 1-9, wherein, Y is CN.
13. according to the described compound of claim 1-12, wherein, X is-NR ' R ".
14. according to the described compound of claim 1-12, wherein X is-OR " '.
15. compound according to claim 14, wherein X is-OH.
16. compound according to claim 14, wherein X is-OCO-R 1
17. compound according to claim 16, wherein, R 1Be C 1-3Alkyl.
18. compound according to claim 13, wherein R ' is H.
19. compound according to claim 13, wherein R ' is-COR 1
20. compound according to claim 13, wherein, R ' is-SO 2-R 1
21. compound according to claim 13, wherein R " are H.
22. compound according to claim 13, wherein R " are-SO 2-R 3
23. compound according to claim 13, wherein, R is " for randomly by one or more R 2Substituted C 1-4Alkyl.
24. compound according to claim 13, wherein, R " is-(CR aR b) n-R 2Each R aWith each R bBe independently selected from H, hydroxyl and methyl, perhaps be connected to the R on the identical carbon atoms aAnd R bForm oxo together; And n is 0,1,2 or 3.
25. compound according to claim 24, wherein n is 2.
26. compound according to claim 25, wherein, R 2For-OH ,-NH 2,-NHR 1,-N (R 5R 5) or-COOH.
27. compound according to claim 22, wherein, R 3For randomly by one or more R 2Substituted C 1-4Alkyl.
28. compound according to claim 22, wherein Y is CN.
29. compound according to claim 27, wherein, R 3For-C 2H 5-N (R 5R 5) or-CH 2-CO-N (R 5R 5).
30. compound according to claim 28, wherein, R 3Be C 2H 5-O-R 1
31. compound according to claim 12, wherein, X is-NH-CO-N (R 5R 5).
32. compound according to claim 1, wherein, said compound is selected from compound 1-55:
Figure FPA00001577340300041
Figure FPA00001577340300051
Figure FPA00001577340300061
Figure FPA00001577340300071
Figure FPA00001577340300081
Perhaps its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
33. compound according to claim 32, it is selected from compound 8,13,29,33,37 and 49:
Figure FPA00001577340300092
Perhaps its pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate or solvate.
34. a pharmaceutical composition, it comprises compound described in the claim 1-33 and suitable excipient.
35. a drug regimen, it comprises the compound described in the claim 1-33 and second medicine.
36. drug regimen according to claim 35, wherein, the medical indication of said second medicine is treatment multiple sclerosis, graft rejection or acute respiratory distress syndrome.
37. each described compound is used to prepare the purposes of medicine among the claim 1-33.
38. the method for an activation or exciting 1-phosphoric acid sphingol receptor subtype 1, it comprises the step that said receptor subtype 1 is contacted with described compound of the claim 1-33 of effective dose or the described composition of claim 34-35.
39. according to the described method of claim 38, wherein, described compound activates or exciting 1-phosphoric acid sphingol receptor subtype 1 reaches the degree that is higher than said compound activation or exciting 1-phosphoric acid sphingol receptor subtype 3.
40. according to the described method of claim 38, wherein, said 1-phosphoric acid sphingol receptor subtype 1 is handled in the mammalian body of living.
41. need the activation of 1-phosphoric acid sphingol receptor subtype 1 or the method for exciting illness in the medical treatment that a kind is treated the patient, this method comprises that to be enough to be that the patient provides frequency and the duration of beneficial effect use the described compound of claim 1-33 from effective dose to the patient.
42., wherein, activate or exciting S1P hypotype 1 acceptor is that needs are gone up in medical treatment with respect to other subtype-selective of S1P acceptor according to the described method of claim 41.
43. according to claim 41 or 42 described methods, wherein, said illness comprises multiple sclerosis, graft rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome (ARDS).
44. one kind is used for the synthetic method that the hexa-atomic saturated rings of naphthane part has the naphthane compound partly of chiral carbon that is included in, wherein, said compound is about the enrichment of said chiral carbon enantiomer, and said method comprises the steps:
(i) compound that comprises the naphthane part is provided, needs the substituted ring carbon of chirality on this carbon, to be replaced in the hexa-atomic saturated rings of wherein said naphthane part by oxo;
(ii) make the reaction of this compound and chiral reagent with before be connected the carbon place formation chiral centre of the naphthane part of oxo group.
45. according to the described method of claim 44, wherein said chiral reagent be RuCl (cymene) [(R, R)-Ts-DPEN] or RuCl (cymene) [(S, S)-Ts-DPEN].
46. according to the described method of claim 44-45, wherein, the said compound that comprises naphthane part that in step (i), provides contacts with chiral reagent to form the compound of formula VI-R or VI-S in (ii) in step:
Figure FPA00001577340300111
Wherein, Z be-CN ,-Cl or-CF 3
47. according to the described method of claim 46, wherein Z is-CN.
48. according to claim 46 and 47 described methods; Wherein, said method further comprises the step of the azido naphthane of chiral configuration upset formation formula VII-S or VII-R through handling the chiral carbon that is arranged in the hexa-atomic saturated rings of naphthane part that connects oxo group before formula VI-R or VI-S compound make it with diphenyl phosphate azide (DPPA):
Figure FPA00001577340300112
Wherein, the azido substituting group substituted hydroxy substituting group in the hexa-atomic saturated rings of said naphthane part, and connect the substituent chiral carbon of azido and have and configuration opposite when said chiral carbon connects hydroxyl substituent before.
49. according to the described method of claim 48; Wherein Z is-CN; And said method further may further comprise the steps: make the intermediate of VII-R or VII-S with the protectant reaction formula VII-R of gained protection form or VII-S intermediate reacted on the phenyl carbons that is connected Z, to form hydroxyamidines with azanol or hydroxylamine hydrochloride through (a), the compound of this reaction gained has formula VIII-R or VIII-S:
Figure FPA00001577340300113
(b) intermediate of formula VIII-R or VIII-S is contacted to form the compound of formula IX-R or XI-S with coupling agent with substituted benzoic acid:
Figure FPA00001577340300114
Wherein, X is OH, N 3, NH-PG, NH 2Or NR ' R "; PG is a blocking group; R ' is H, C 1-4Alkyl, primary hydroxyl C 1-4Alkyl ,-SO 2-R 1Or-CO-R 1R " be H ,-SO 2-R 3, randomly by one or more R 2Substituted C 1-4Alkyl is perhaps randomly by R 4Substituted loop section, wherein this ring portion is divided into piperidyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazole radicals or phenyl; R aBe low alkyl group, and R 1, R 2, R 3And R 4It is identical with the definition in the claim 1,
Be formed on substituted 1,2 on the naphthane part, 4-oxadiazole.
50. according to the described method of claim 49, the compound of formula IX-R or IX-S has following structure:
Figure FPA00001577340300121
51. according to the described method of claim 49-50, wherein, said coupling agent is for comprising the mixture of hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC).
52. according to the described method of claim 44-51, wherein, the compound that in step (i), provides is:
Figure FPA00001577340300122
53. according to the described method of claim 42-52, wherein the enantiomer enrichment of the compound that is included in the naphthane part that has chiral carbon in the hexa-atomic saturated rings of naphthane part of gained is at least 90%.
54. according to the described method of claim 53, wherein, the compound enantiomer enrichment of gained is at least 95%.
55. according to the described method of claim 54, wherein, the compound enantiomer enrichment of gained is at least 98%.
56. according to the described method of claim 55, wherein, the compound enantiomer enrichment of gained is at least 99%.
57. compound that is selected from the following compound:
Figure FPA00001577340300131
58. one kind is used for the synthetic method that the hexa-atomic saturated rings of naphthane part has the naphthane compound partly of chiral carbon that is included in; Wherein said compound is the enantiomer enrichment with respect to said chiral carbon, and said method comprises the step that the described compound of claim 57 is provided.
59. according to the described method of claim 58, wherein, the said compound that is included in the indane part that has chiral carbon in the indane five-membered ring partly is the compound of formula IX-R or XI-S:
Figure FPA00001577340300141
Wherein, X is identical with the definition in claim 1.
60. according to the described method of claim 59, wherein, the compound of said formula IX-R or XI-S is the described compound of claim 1-33.
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